T lymphocytes are extensively studied cell types in the tumors and are second most important cells found in the human tumors. CD8⁺ T exert their effect on priming and upon activation by the antigen-presenting cells (APCs), these cells get differentiated into CTLs and exhibit antitumoral activity via exocytosis of the granzyme and perforin-containing granules exerting antitumoral activity whereas cytotoxic CD8⁺ T cell reinforced by CD4⁺ T helper (Th1) cells by producing Tumor necrosis factor alpha (TNF-$\alpha$), Interleukin 2 (IL2) and IFN-$\gamma$, increases the anticancer function of macrophages and NK cells thus eliminating the tumor and linked with better prognosis and overall survival in malignancies [8, 9]. Histopathology studies for the tumors have shown that the T cells associated with tumors predominantly occur in the hypoxic tumor core. Higher T cell infiltration in tumors has been advantageous in the prognosis of lung, breast, gastric, renal, prostate, ovarian and colorectal cancer (CRC) [8].

In a process involving T cells, the cancer cells which express immunogenic antigens would be identified and destroyed in the initial tumor development stage. The less immunogenic tumor cells resist T cells and are not killed. This process is called as cancer immune editing. These survived cells adopt an immune resistant phenotype. This results in the resistance to the local cytotoxic response from the NK cells, T cells, tumor associated macrophages (TAMs) and tumor associated neutrophils (TANs). As tumor starts growing, the TME evolves, and new antigens are formed and the immune system capacity to prepare many T cells increases directing them to the tumor modifying the efficiency of tumor suppression. Cancer cells and TME suppress anticancer activity by involving recruiting regulatory CD4⁺ T cells (Tregs) and immune checkpoints as the immune system prevents cancer growth. Tregs exist in higher amounts in the TME, and its function is to suppress the anticancer activity. Tregs inhibit T cell stimulation and anticancer immune response in lung and breast cancer [8, 9]. Tregs have a main role in the advancement of breast tumor by suppressing the anticancer activity by various mechanisms [8].

The immunotherapy utilizes the antigen specific T cell attack for fighting against tumor. The key problem is recognizing the phenomenon by which tumor cells undergo changes to avoid attack by T cells. Furthermore, understanding the heterogeneity of the tumors will help in developing better immunotherapies for cancer.

B cells possess both negative and positive roles in the immunity against cancer [9]. There are reports on the efficiency of B cells increasing the T cell functionality in the mouse models in squamous carcinogenesis [10]. Presence of CD20⁺ B cells in cervical carcinoma [11], gastric cancer [12], breast [13], lung cancer [14], prostate cancer [15] is linked with better prognosis. Importance of B cells in cancer therapy poorly known to date. Reports have indicated that B cells support and promote tumor growth. Ammirante & co-workers (2010) [16] demonstrated that B cells, employed by chemokine C-X-C motif ligand 13 (CXCL13), facilitate the prostate cancer development by producing lymphotoxin. de Visser et al. (2005) [10] showed that the tumor progression was found to be decreased when the mature B cells were absent. The adoptive transfer of B cells was found to increase angiogenesis, chronic inflammation and tumor growth. Though lymphotoxin could aid in tumorigenesis, the cytokine produced by B cells can aid in the tertiary lymphoid organs (TLOs). The number of TLOs correlates with the advantageous results in human and mouse models. Occurrence of B cells in TLOs has helped in the prognosis leading to the longer survival in cancer [17]. B cells possess ability to make cytokines, chemokines and also recruiting the immune cells to the TLOs, secondary lymphoid organs (SLOs) and other important effector sites [17].

The portion of B cells inducing immunosuppression are known as regulatory B cells. Immunogenic chemotherapy in human and mouse prostate cancer need B cell subtype removal, IL, plasmocytes expressing IgA, and Programmed Death-Ligand 1 (PD-L1) the presence of which is dependent on the TGF-$\beta$ receptor signalling which encourage CD8⁺ T cell fatigue thereby suppressing the anticancer activities [9].

The role of DCs is to attack the antigens found in configuration of peptide major histocompatibility complex (MHC) and presenting those antigens to the T cells [9]. Stimulation of immune cells facilitates inflammation and disturbs tissue homeostasis and also is linked with the cancer development. Main mechanism is controlled by myeloid-derived IL-6, that stimulates the transcription factors namely, nuclear factor-$\kappa$B (NF-$\kappa$B) and signal transducer, activator of transcription 3 (STAT3), as reported in various cancer models. STAT3 and NF-$\kappa$B are stimulated in DCs while presenting the antigens to lymphocytes; and hence, DCs could be anti- or pro-tumorigenic based upon the context. Numerous types of DCs exist and perform specific functions: (a) DC antigen presentation and processing (b) CD8⁺ T cell immunity is improved by epidermal Langerhans cells, and humoral immunity is supported by dermal/interstitial (CD14⁺) DCs and (c) plasmacytoid (pDCs) that secrete large amounts of type I IFN [9]. There are reports on selective reduction of CD14⁺ DCs in comparison to the normal lung tissue correlating with the diminished T-cell and NK activity favoring tumor growth. When the maturation signals are absent, DCs occur in the immature condition (iDC). Various signals like microbe linked molecular patterns or damage linked to the molecular patterns could result in the maturation of iDC [18].

NK cells display a very fast cytolytic activity to the infected cells. These cells possess stimulatory and inhibitory receptors onto their surface and are used in immune surveillance and recognize peptides presented on the MHC molecules. These NK cells help not only in destroying the cancer cells by releasing cytolytic granules but also release cytokines and chemokines stimulating the immune response [8, 9, 19, 20]. Main characteristic of NK cells is their inhibition by the receptors binding to MHC Class I and because of this reason NK cells destroy tumor cells lacking MHC-I. In normal cells, the receptors binding to the MHC-I molecules possess an inhibitory effect on the NK cell function [9]. Also NK cells could negatively affect anticancer responses by modulation of T and DC cells [9]. Glasner & group (2018) [21] showed a new way by which NK cells modulate immune response. A study reported that the NK cytotoxic receptor activation in mouse and NKp46 in human leads to enhanced production of IFN-$\gamma$ modulating fibronectin 1 expression on tumor cells preventing the metastasis [21]. Various tumor associated factors like TGF-$\beta$1, prostaglandin E2 (PGE2), indoleamine 2, 3-dioxygenase (IDO) and IL-10 prepared by various tumor-infiltrating immune cells which include myeloid-derived suppressor cells (MSDC), DC, Treg and M2-macrophages can affect the activity of NK cell activity [9]. Tumor produced IL-15 recruit dense granulated NK cells to the large tumors where they eliminate the established tumors successfully. NK cells have been used successfully in lung cancer [22], triple negative breast cancer (TNBC) [23], and neosarcoma [24].

The TAMs possess a main function in the cancer associated inflammation. Macrophages play a vital role in every step starting from the early phase to the metastatic cancer progression stage to the resistant to therapy stage. According to the clinical and pre-clinical data, TAMs are linked with the poor prognosis and reduced survival of cancer patients. Macrophages on activation are known as pro-inflammatory (M1 type) facilitated by IFN-$\gamma$, TNF-$\alpha$ and or anti-inflammatory (M2 type) facilitated by IL-13 or IL-4 [8, 9]. During cancer, anticancer macrophages show M1-polarization playing an important role in destruction of tumor cells. As the cancer grows, TME provokes protumorigenic M2-like polarization of TAMs and acts by contributing to immune suppressive TME and hampering the functionality of T cells [25]. TAMs facilitate tumor growth and spread by various ways like promoting lymphangionesis and angiogenesis, enhancing cancer metastasis, augmenting the immunosuppression of anticancer immune cells, remodelling the exracellular matrix. By secretion of TGF-$\beta$, IL-10 and TAMs facilitate immunosuppression and impair the effector T cell activity, and inhibit maturation of DC [20]. The protumorigenic activity of TAMs is also associated with the colony-stimulating factor (CSF)-1 production by tumor cells, which leads to release epidermal growth factor (EGF) and manipulate cancer cells favoring cell migration, extravasation, and metastasis. Additionally, TAMs were reported to negatively impact T cell activities in ovarian cancer and hepatocellular cancer [9]. Various biological agents for targeting macrophages in cancer are successfully developed and tested in the cancers demonstrating a potential to reach clinical trial stage [26].

Neutrophils comprise approximately 50–70% of the leukocytes and display primary defense against any infection. In the TME, the key phenomena facilitate polarization of neutrophils in the different subpopulations viz. N1 (antitumorigenic), N2 (protumorigenic), and TANs [9]. TANs are thought to be associated with the inflammation during the start and progression of cancer. In a study reported by Chang & co-workers (2014) [27] in a lung adenocarcinoma model in mouse, IL-17 responsive TANs were found to encourage cancer growth. Neutrophil elastase is an enzyme secreted at the inflammation site which encourages angiogenesis, tumor invasion and proliferation [28, 29]. Recent reports have showed that the neutrophils display a key function in the awakening of dormant cells and tumor metastasis growth [30]. TGF-$\beta$ produced by tumor associated fibroblasts (CAFs) is found to facilitate tumor growth by activating N2 and suppressing N1 cells [9, 30]. Type I IFN possess an opposite effect than that of TGF-$\beta$. IFN-$\beta$ helps in mediating an anticancer activity by suppressing the expression of factors responsible for angiogenesis viz. matrix metalloproteinases (MMP9) and vascular endothelial growth factor (VEGF) helping limit the tumor growth. Additionally, IFN-$\beta$ help in recruitment of neutrophils and their lifespan in the tumor [31, 32, 33]. N2 TANs via MMPs and interleukin (IL)-1$\beta$ secretion aids in activation of endothelial cells, inhibition of NK cells and promotion of plasticity of cancer cells and cancer spread by migration [9]. In the patients with melanoma, higher amounts of neutrophils and the neutrophil to lymphocyte ratio is linked with the reduced responsiveness to anti-cytotoxic T lymphocyte antigen (CTLA-4), depicting the role of these cells in immunosuppression. Better understanding about how and where the neutrophils are programmed and re-programmed to become protumor or antitumor will aid in the rational design of the targeted therapy.

Pathological interactions between immune components within the TME and cancer cells gives rise to an immunosuppressive network because of which attack by the host immune cells are shielded and tumor growth is promoted (Fig. 1). The complex network formed by immune cells (T regulatory cells, MDSCs, TAMs, DC) in the TME helps to escape the cancer cells to immune surveillance [38]. The immunosuppressive mechanisms of cancer cells are manifold which avoids immune recognition and reduces or disables effector T cells by mimicking important signalling pathways to gain immune tolerance, altering antigen presenting machinery, secreting immunosuppressive cytokines and inhibitory factors, to name a few [39]. Extrinsic and intrinsic factors, such as an increase in MDSCs and T regulatory cells or antigen loss tumor variants selection, both favour immune surveillance escape. The interaction of immunosuppressive cells (T regulatory cells, MDSCs, TAMs) with effector T cells is critical in understanding the mechanism of immunosuppression [40]. Sub-population of T regulatory cells builds up in the tumor tissues and hinder antitumor responses in cancer patients although they can control immune homeostasis in peripheral tissues [41].

Tumor progression is promoted by an enrichment of immunosuppressive cells in “cold tumors” referring to non-T cell inflamed tumors. Whereas tumor regression can occur in “hot tumors” which are T cell-inflamed in which the epitopes of tumor cells can be identified by tumor infiltrating T cells [42, 43]. High expression of the CAF membrane protein FAPa in epithelial tumors might reduce hypoxic necrosis as demonstrated in vitro which could relate to tumor growth control in vivo, thus throwing light on the importance of these cells as immunosuppressors in the TME [44]. The abnormal metabolism of tumor cells along with microenvironmental factors like hypoxia, acidic conditions, and high interstitial fluid pressure accelerates survival of the tumor. High interstitial fluid pressure prevents immune cells recruitment in the tumor site [45]. Hypoxia promotes vascularization, the activation of several signalling pathways, and the expression of pro-angiogenic factors, which leads to metastasis and tumor aggressiveness [46]. The development of immunosuppressive cells is promoted in tumor’s low pH which also inhibits T cell infiltration and activation of TAMs [47].

Extensive research through pre-clinical studies and clinical trials have led to a vast exploration of immunotherapy against cancer. However, in the overall population and clinical setting, the response rates towards immunotherapy are quite low for majority of patients. Resistance to immune therapy can be conceptualized as primary, adaptive, and acquired. Some patients fail to show any response from the treatment, which is termed as primary resistance, while some stop responding after an initial period of benefit which is termed as acquired resistance. In the case of adaptive resistance, the immune system recognises the cancer, but the immune attack is not successful because the cancer can protect itself by adapting to the immune attack. Immune therapy was unsuccessful in several common types of cancers and variance in response has been observed in distinct tumors of the same patient as well. The resistance mechanisms and immune responses of patients are very dynamic and depends on many factors related to treatment interventions. Intrinsic mechanisms for resistance to immunotherapy include lack of tumor antigens and deficiency in T cell recognition, alterations in signalling pathways (Mitogen-Activated Protein Kinase (MAPK), Wingless-related integration site (WNT), IFN-$\gamma$), constitutive expression of PD-L1 or absence of antigenic proteins/antigen presentation. Extrinsic factors comprise of components of the TME other than the tumor cells such as, lack of T cells due to exhaustion or phenotype change and immunosuppressive cells [122].

The DCs play a pivotal role in regulating and coordinating immune responses within the body [130]. As professional APCs, they possess a distinctive capability to initiate, sustain, and modulate T cell responses, thereby bridging a link between the adaptive and innate components of the immune system. This orchestration is vital in combating tumor cells, where the immune system’s innate response serves as the initial defence, followed by the adaptive response [131].

One of the critical functions of DCs is to serve as a link between these immune responses by introducing antigens to T cells, triggering cell activation, and augmenting immune reactions [123]. DCs hold paramount importance in stimulating antitumor immunity by recognizing various entities like microbes and tumor cells, aided by specialized receptors on their surfaces. DCs effectively internalize antigens after recognition via efficient phagocytic and endocytic mechanisms. Subsequently, they process these captured antigens to facilitate both class I and II presentation. This process triggers an upsurge in DCs’ ability to present these antigens to T cells, amplifying the immune response [132].

The maturation of DCs is stimulated by tumor-derived molecules, including high mobility-group box 1 proteins and heat shock proteins. Along with proinflammatory cytokines generated by immune cells within the TME. Additionally, the maturation is influenced by proinflammatory cytokines released by immune cells within the TME. Mature DCs migrates from the tumor site to SLOs, where they instigate the activation of tumor-reactive CD8⁺ CTLs and CD4⁺ T cells. The CD8⁺ CTLs play an essential role in recognizing and eradicating tumor cells presenting peptides derived from TAAs in conjunction with human leukocyte antigen (HLA) class I molecules [133]. Simultaneously, CD4⁺ T cells aid in enhancing the capacity of DCs to generate CTLs through interactions like CD40-CD40 ligand and provide support for the maintenance and development of these CTLs through cytokine secretion, such as IL-2 [134].

The use of antigen-pulsed DCs, which are prepared by in vitro loading of specific antigens onto DCs, represents a potential method for evoking immune responses in cancer patients and also in individuals suffering from a variety of clinical diseases [135, 136]. The process involves the expectation that DCs will identify, uptake, internalize, and process antigens in vitro, and subsequently, these antigen-loaded DCs might migrate directly to lymphoid tissues, activating lymphocytes and triggering TAAs-specific immunity [137].

Immature DCs demonstrate particular efficiency in capturing tumor-derived material in peripheral tissues. They internalize these antigens, undergo processing, and upon migrating to T cell-rich zones in secondary lymphoid tissues such as lymph nodes, they undergo maturation and express co-stimulatory molecules. Besides their exceptional capability to elicit and stimulate T cell responses, DCs significantly enhance natural killer cells immunomodulatory and cytotoxic potential, which contribute significantly to eradicating tumor cells. Additionally, DCs have the ability to directly mediate cytotoxicity against tumor cells, demonstrating their multi-faceted antitumor effects [138].

The preparation of DCs is primarily achieved by isolating them from peripheral blood mononuclear cells (PBMCs), with monocyte-derived DCs (moDCs) being more commonly employed, given the restricted availability of CD34⁺ precursors [139]. These cells are initially created as immature DCs using granulocyte macrophage colony-stimulating factor (GM-CSF), IL-4, or IFN-$\alpha$, and subsequently matured using various activation stimuli such as CD40L, LPS, IFN-$\alpha$, IFN-$\gamma$, TNF-$\alpha$, and TLR agonists [140].

Recent advances in DC-based immunotherapy involve employing neoantigens for loading DCs aiming to elicit more robust immune responses and the development of rapid, standardized, and automated production of DC vaccines comprising natural DC subsets. These advancements hold promise in improving the quality of DC vaccines and enabling multicentre trials. Combining DC vaccination with other therapeutic approaches such as monoclonal antibodies against chemotherapy, immune checkpoints, cytokine-induced killer cells (CIK), radiotherapy, or nanoparticles shows potential in further enhancing anticancer immunity. However, the optimal combination treatment regimen requires further investigation and refinement through comprehensive research in this domain [141].

Numerous clinical trials are currently exploring the therapeutic potential of DC vaccination in various cancer types, signalling a significant advancement in cancer treatment strategies. These trials represent a diverse array of cancer types and investigate the safety and effectiveness of DC vaccination either as a standalone therapeutic approach or in combination with ICIs, aiming to augment anti-tumor immune responses. For example, a Phase III trial (NCT04855275) focuses on advanced melanoma, assessing the synergistic effects of an autologous DC vaccine combined with PD-L1 blockade across multiple sites in the United States and Europe. Simultaneously, a Phase II trial (NCT03918174) is evaluating DC vaccination in tandem with nivolumab for advanced non-small cell lung cancer (NSCLC) in various locations in the US and Canada. In a parallel effort, a Phase II trial (NCT04940393) investigates the combination of DC vaccination with pembrolizumab for metastatic CRC, involving multiple sites across the US and Australia. Additionally, a Phase I/II trial (NCT04656486) targets pancreatic cancer antigens with DC-based vaccines in the United States, while a Phase I/IIa trial (NCT03541087) explores DC vaccination in advanced SCCHN patients.

The phase I study (NCT01730118) explored a Human Epidermal Growth Factor Receptor 2 (HER2)-targeting DC vaccine in metastatic cancer and high-risk bladder cancer expressing HER2. It had two parts: one for bladder cancer progression after standard treatment or no conclusive evidence of disease, and another for cancer progression after anti-HER2 therapy. The vaccine, generated from autologous monocytes transduced with AdHER2, was administered in five doses. Among 33 patients across different dose levels, 33.3% showed clinical benefit, including one complete response, one partial response, and five stable diseases. No cardiac toxicity was observed, and adverse events were mainly injection-site reactions. After three doses, 23.1% displayed an antibody response, and 90.9% exhibited anti-HER2 responses in lymphocytes, with multifunctional immune responses in 72.7%. The AdHER2 DC vaccine showed promising preliminary clinical benefit and immunogenicity, indicating potential for further combined therapeutic applications [142].

Adoptive T cell therapy represents a groundbreaking approach in cancer treatment by leveraging a patient’s immune cells to target and eliminate cancer [143]. TILs are first derived from the patient’s tumor tissue. These TILs, harbouring potential antitumor activity, are then cultured and developed ex vivo before subsequent reintroduction into the patient as portrayed in Fig. 2A. Despite showing promise in some cases, TIL therapy presents logistical challenges due to the difficulty in isolating and expanding sufficient TILs for effective treatment, along with the need for substantial resources and time.

Researchers have turned to genetic engineering to create more effective cancer-targeting T cells to overcome these limitations. This involves modifying a patient’s T cells outside the body to express specific receptors capable of identifying and attacking cancer cells. Two primary types of receptors used in adoptive T cell therapy are CARs and T cell receptors (TCRs) depicted in Fig. 2B.

TCRs are genetically engineered to detect unique cancer epitopes presented on the tumor cell surface by major MHC molecules. This personalized approach aims to create TCRs tailored to a patient’s specific cancer type, enhancing specificity in targeting tumor cells while mitigating damage to healthy tissues.

On the other hand, Chimeric antigen receptor (CAR) T therapy implies modifying T cells to express CARs that combine an antibody’s extracellular domain’s antigen-recognition capability with T cell signalling domains. This configuration allows CAR-T cells to recognize cancer-specific antigens independently of MHC molecules, broadening the range of tumor targets [144, 145, 146, 147].

Despite the potential of TILs and genetically modified T cells, there are challenges. TIL therapy’s personalized nature limits its scalability and efficiency due to the complex and costly process of isolating and growing these cells. Additionally, the administration of high-dose IL-2 alongside adoptive transfer may lead to severe side effects.

Genetically modified TCRs have shown promise against certain cancers, yet they may also cause off-target effects, damaging healthy tissues expressing the targeted antigen. CAR-T therapies, targeting antigens like CD19, have gained approval for certain types of leukemia and lymphoma, demonstrating remarkable efficacy, but they can be linked to adverse effects like cytokine release syndrome (CRS) and neurotoxicity [35, 48].

Continued research aims to improve the effectiveness and safety of adoptive T cell therapy. Scientists explore strategies like synthetic sensors and switches to control T cell activity more precisely and are also investigating genome editing and cellular engineering techniques to optimize the therapeutic potential of these T cells that have been genetically modified. Advancements in this field may lead to more efficient and safe cancer treatments in the future.

The overactivation of antigen-specific T cells, while a vital part of the immune response, can sometimes lead to serious side effects, including CRS and damage to healthy tissues. The immune system employs a variety of inhibitory mechanisms to regulate T cell activity.

Inhibitory receptors like CTLA-4 and PD-1, along with PD-L1, play vital roles in controlling T cell activation. Additionally, regulatory T cells (Tregs) expressing CD4, CD25, and forkhead box protein 3 gene (FOXP3), also IL-2-mediated activation-induced cell death (AICD), contribute to immune regulation [148].

CTLA-4 and PD-1/PD-L1 checkpoint blockade function at various phases of the immune response and exert distinct effects on T cells. CTLA-4 acts at initial stage, affecting T cells in lymphoid organs, whereas PD-1/PD-L1 modulation occurs in peripheral tissues during later immune responses. PD-1 blockage revives dormant T cells to reinstate their anticancer activity, while inactivation of CTLA-4 leads to the stimulation and proliferation of new T cell clones and diminishes the suppressive action of Tregs [149].

When comparing PD-1/PD-L1 and CTLA-4 blockades, PD-1/PD-L1 inhibition has a more targeted effect on antitumor T cells. Continuous exposure to antigens enhances the therapeutic effectiveness of PD-1/PD-L1 blockade with reduced toxicity. Several FDA-approved medications, such as Pembrolizumab (Keytruda®), Nivolumab (Opdivio®), Cemiplimab (Libtayo®), Avelumab (Bavencio®), Atezolizumab (Tecentriq®), and Durvalumab (Imfinzi®), target PD-1 or PD-L1, and are utilized in the treatment of various cancers including Hodgkin’s lymphoma [35].

These immunotherapies that target PD-1 or PD-L1 have revolutionized cancer treatment by releasing the immune system’s ability to fight cancer. They have shown remarkable efficacy in certain cancers, offering durable responses and improved survival rates for many patients, while their selective action on specific T cell subsets minimizes adverse effects compared to traditional chemotherapy. However, further research continues to refine these therapies to optimize their efficacy and mitigate potential adverse effects.

Recent trials using increased lymphodepletion before infusing autologous TIL achieved impressive response rates of 49% to 72%. Persistence of infused cells, their characteristics, and the removal of suppressor cells before treatment contribute to its success. ACT’s (Adoptive cell therapy’s) bility to generate durable responses across various sites signifies its potential. Ongoing efforts focus on refining ACT by modifying lymphocyte genetics, altering cell functions, and exploring vaccines to stimulate transferred cells [150].

The ELIANA trial, using Tisagenlecleucel in paediatric and young adult individuals diagnosed with CD19⁺ relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), yielded impressive results, with an overall remission rate of 81% at three months. Moreover, the survival probability at six months reached a notable 73%. Meanwhile, the ZUMA-1 trial, involving patients with primary mediastinal B-cell lymphoma (PMBCL), diffuse large B-cell lymphoma (DLBCL), or transformed follicular lymphoma (TFL), demonstrated encouraging outcomes, showing an 82% overall remission rate. However, the 18-month survival rate was observed to be 52% [151, 152].

Notably, the FDA’s approval of Axicabtagene Ciloleucel for treating various lymphomas in adults and Tisagenlecleucel for refractory or relapsed ALL in young patients, along with certain cases of DLBCL in adults, marked significant milestones in CAR T-cell therapy for hematological malignancies.

The discussion around CAR T-cell therapy for solid tumors highlighted substantial challenges. While specific trials were not detailed, the obstacles in this realm are multifaceted. They encompass difficulties in selecting appropriate Tumor-associated antigens (TAAS) crucial for effective therapy, inadequacies in T cell infiltration into tumors, and the hostile nature of TMEs. Furthermore, issues related to T cell self-regulation add complexity to this therapeutic approach [132].

Moreover, the presence of toxicities associated with CAR T-cell therapy further underscores its complexity. These include on-target off-tumor effects such as CRS, anaphylaxis, and neurotoxicity. These complexities and limitations pose significant hurdles to extending CAR T-cell therapy successfully to the treatment of solid tumors.

Apoptosis, once viewed as a non-inflammatory process, is now known to potentially evoke an immune response under specific conditions, termed immunogenic cell death (ICD). This phenomenon occurs when cells undergoing apoptosis release specific substances, including ATP, HMGB1, and calreticulin, which signal the immune system to detect and eliminate preapoptotic tumor cells [153, 154]. Recent research has revealed that certain chemotherapeutic agents and oncolytic viruses (OVs) induce ICD by releasing immunomodulatory molecules that activate immune cells, leading to a robust adaptive immune response against cancer cells.

Various cellular processes, such as components associated with the endoplasmic reticulum (ER) stress, DNA damage response, and apoptosis pathways, contribute to the immunogenicity of tumor cells. These processes trigger the release of danger signals and enhance immune activation, crucial for activating effective antitumor immune responses. Despite the historical belief that apoptotic cell death was immune-tolerant, it’s now understood that apoptotic cells produce molecules which are known as damage-associated molecular patterns (DAMPs), which possess potential anticancer properties by stimulating immune recognition.

It is crucial to comprehend the process of ICD in relation, to cancer immunotherapy. Different inducers of ICD have been categorized into type I and II based on their mechanisms of inducing apoptotic cell death and ER stress. Type I inducers include chemotherapeutic agents, specific antibodies and inhibitors while type II inducers consist of photodynamic treatments and certain viruses. These inducers hold promise in modulating tumor cell responses and triggering immune reactions against cancer, paving the way for Oxaliplatin is a chemotherapy drug that falls under the platinum compounds class and is used to treat variety of cancers, including CRC. Its unique mechanism of action includes the induction of ICD, which is a sort of PD that activates the immune system. This process may be beneficial in the treatment of cancer as it helps to eliminate cancer cells effectively. Several innovative therapeutic approaches have been developed using oxaliplatin in cancer treatment [155].

A recent study has shown that oxaliplatin triggers a process called ICD in CRC cells. This process involves the exposure of calreticulin (CRT), a protein involved in calcium regulation and ER stress response, to the extracellular environment. CRT then moves to the surface of cancer cells, initiating a signal cascade to DCs, immune cells tasked with capturing and presenting antigens to T cells. Additionally, oxaliplatin leads to the liberation of high-mobility group box 1 (HMGB1), a protein that binds to TLRs on DCs and macrophages (immune cells that phagocytose and process antigens). These events enhance DCs and macrophages’ ability to present antigens, thereby stimulating T cell activation and cytotoxicity against cancer cells [156].

The study found that oxaliplatin-induced ICD was more effective than cisplatin-induced ICD in CRC cells. Both drugs were equally efficient in releasing HMGB1. However, only oxaliplatin induced pre-apoptotic CRT exposure while cisplatin did not. Research also demonstrated that CRT exposure by oxaliplatin-treated CRC cells induced an antitumor immune response in vivo, and this response was reduced by knocking down CRT or HMGB1 expression or function. Moreover, they found that patients with advanced CRC who received oxaliplatin-based chemotherapy had a higher frequency of TLR4 loss-of-function allele than the general population, which was associated with reduced progression-free survival [156].

Vaccination is a cornerstone in disease prevention, with two main types: preventive and therapeutic. Preventive vaccines work by generating specific antibodies and long-term memory B cells to stop the spread of infections. Therapeutic vaccines, on the other hand, aim to target and eliminate the underlying cause of a disease, such as virally infected cells or cancer cells, to treat the condition. Their effectiveness often hinges on antigen-specific CD8⁺ T cells, which produce CTLs responsible for identifying and destroying affected cells [157].

Various strategies exist in the domain of anticancer vaccination as depicted in Fig. 3. These strategies aim to leverage the immune system’s capability to identify and eliminate malignant cells while promoting long-term immunity [48, 125, 158]. They include:

• Whole Cell or Tumor Lysate Vaccines: These vaccines use irradiated tumor cell lines combined with immunostimulatory cytokines. While showing promise, their efficacy can vary. Various cytokines such as GM-CSF, IFN-$\alpha$, IL-2, and IL-12 have been investigated as adjuvants in these vaccines. A notable example is the granulocyte macrophage-colony-stimulating-factor (GM-CSF) secreting colon cancer (CRC) vaccine (GVAX) vaccine by Cell Genesys, Inc. in San Francisco, CA, which has undergone phase III trials for prostate cancer. This particular prostate cancer vaccine comprises two allogeneic prostate cancer cell lines that are genetically engineered to produce GM-CSF [159, 160].

• DNA-Based Vaccines: These vaccines use plasmid DNA to induce antigen-specific cellular and humoral immunity. They have the advantage of delivering multiple antigens in a single immunization, activating various forms of immunity [161]. Neoepitope-based cancer vaccines show promise in igniting tumor-specific immune responses but face challenges due to cost and time constraints. Research using DNA-based neoepitope vaccines demonstrated protection against colon tumor-26 (CT26) tumors and a robust CD4⁺ and CD8⁺ T-cell response targeting mutated epitopes. Administering multiple neoepitopes in a single plasmid proved more effective than subgroup plasmids. While therapeutic DNA vaccination post-tumor inoculation didn’t show significant effects, combining anti-PD-1 ($\alpha$PD-1) therapy with suboptimal doses of the DNA vaccine exhibited superior tumor control. However, challenges persist in modulating the tumor environment and addressing potential immune resistance. Emerging DNA vaccine technologies hold promise for future clinical use, highlighting DNA’s potency as a versatile neoepitope delivery method for comprehensive anti-tumor immunity [162].

• Peptide-Based Vaccines: These vaccines utilize peptides derived from specific antigens presented by MHC molecules on cell surfaces. They are easy to produce, administer, and monitor but they are limited to specific HLA alleles. The first successful clinical response to peptide-based immunotherapy utilized peptides obtained from the melanoma-associated antigen (MAGE-3), showcasing the potential for tumor regression with this approach. Peptide-based vaccines offer various advantages, including easy and cost-effSSective production in clinical settings, simple patient administration, non-toxic nature, and the ability to monitor antigen-specific anti-tumor immune responses. However, a significant limitation is that peptides are specific to certain HLA alleles, narrowing the scope of effectiveness. Ideal candidates for peptide-based anticancer vaccines are those obtained from TAAs expressed solely on tumor cells (like HER2, Mucin 1) able to induce a cytotoxic T cell response upon vaccination. Another concern is “tumor escape”, wherein tumor cells can alter antigens or reduce the production of HLA molecules and immunogenic antigens, evading immune detection (cancer immunoediting) [163].

• Protein-Based Vaccines: These vaccines employ whole TAAs in the form of proteins, aiming to be taken in by tissue resident DCs for immune presentation. Adjuvants are often used to enhance immunogenicity. Such proteins are expected to be collected by tissue-resident DC after injection, resulting in their presentation within HLA class II and potentially class I molecules. To enhance the immunogenicity of antigen peptide and protein-based vaccines, they are often combined with adjuvants like incomplete Freund’s adjuvant (IFA), BCG (Bacillus Calmette-Guérin), tetanus toxoid peptide epitopes, diphtheria toxoid, IL-12, and GM-CSF. Additionally, they may be loaded onto DCs generated ex vivo to boost their efficacy in eliciting immune responses [163, 164, 165].

• Heat Shock Protein (HSP) Vaccines: Heat shock proteins (HSPs) serve as intracellular proteins that act as peptide chaperones, including examples like gp96, HSP70, calreticulin, and HSP110. After being released from a cell, APCs can collect these proteins and subsequently display HSP-associated peptides through HLA class I molecules. The presence of extracellular HSPs triggers DC maturation by providing an activating signal to these cells. HSPs can be genetically modified to transport specific TAAs like the E7 protein from the MAGE or HPV antigen. Alternatively, they can be isolated from a patient’s tumor specimens and re-injected to create anticancer vaccines [166, 167].

• Viral Vector Vaccines: Several viruses, engineered to express tumor antigens, can trigger an antigen-specific immune response. They often induce strong immunogenicity, but the development of neutralizing antibodies and side effects limit their use. Various viruses, such as attenuated replication-defective poxviruses (like avipox, canarypox, and fowlpox, virus), herpes virus, adenovirus, and Venezuelan equine encephalitis virus, can be modified to express specific tumor antigens, triggering an immune response targeting those antigens. Compared to other vaccination methods, using viruses tends to generate robust immunogenicity, resulting in a significantly amplified immune response to the antigen encoded. However, the major limitations hindering the widespread use of viral vectors in anticancer vaccinations include the formation of neutralizing antibodies in individuals encountering a specific virus for the first time after vaccination and the substantial side effects associated with virus administration [35, 36].

• Dendritic Cell -Based Vaccines: DCs, as potent APCs, bridge innate and adaptive immunity. Vaccines using protein-pulsed, peptide-pulsed, or viral-vector infected DCs have shown promise in several tumor types. Notably, the first FDA-approved autologous cell vaccine, Sipuleucel-T, specifically targets males with metastatic prostate cancer. This vaccine consists of APCs derived from PBMCs, treated with prostatic acid phosphatase (PAP) linked to GS-CSF [158].

Despite the potential, challenges exist, such as tumor escape mechanisms, limited antigen specificity, and potential side effects associated with certain vaccine types. Ongoing research aims to overcome these hurdles, striving to develop effective and safe anticancer vaccines to improve patient outcomes.

Among the most promising realms in contemporary cancer therapy involves monoclonal antibodies (mAbs), specialized in targeting specific proteins crucial for tumor cell proliferation [168]. Belonging to the IgG class, these biological macromolecules form a burgeoning pharmaceutical pipeline and stand as a pivotal tool in cancer immunotherapy. Engineered replicas of immune system proteins, mAbs aid in eradicating cancer cells by binding specifically to surface antigens on these cells. They trigger immune responses like complement-dependent cytotoxicity (CDC), antigen-dependent cellular cytotoxicity (ADCC), and facilitate antigen cross-presentation. Moreover, they target immunomodulatory receptors such as PD-L1 and CTLA-4, thereby obstructing signal transduction via growth factor receptors (like epidermal growth factor (EGFR) family members), leading to tumor cell elimination [169, 170, 171]. However, for mAbs to be effective, they must overcome obstacles to reach target cell antigens. Intravenous (IV) delivery faces challenges due to varied antigen expression on tumor cells, evasion of the host immune system, and traversal of physical barriers like vascular endothelium, high interstitial pressure, stromal barriers, and epithelial barriers within solid tumors [172]. Monoclonal antibodies for cancer treatment can be classified into two types: naked antibodies, which aren’t combined with any drug, and conjugated monoclonal antibodies, acting as carriers for chemotherapeutic drugs, radioactive particles, or toxins [169].

Rituximab is a monoclonal antibody targeting CD20 on immune cells. Treats lymphomas, leukemias, arthritis, and autoimmune diseases by eliminating specific cells or modulating immune responses [173]. In a study involving follicular lymphoma patients responding to rituximab treatment, two groups were compared: one receiving maintenance rituximab every 3 months and the other rituximab only upon disease progression. Results showed similar disease control among the groups over a 4.5-year median follow-up, with comparable treatment failure rates at the 3-year mark (61% retreatment vs. 64% maintenance). Health-related quality of life remained consistent. The patients in maintenance group received more rituximab doses but experienced infrequent serious side effects (94% overall survival in both groups). Limitations included differences in induction therapy and the study’s design favouring responsive patients for retreatment. However, the retreatment strategy showed promise in avoiding further therapy for responsive patients after rituximab induction [174].

Another study evaluated first-line treatment using monotherapy with trastuzumab in 114 women with HER2-overexpressing metastatic breast cancer. Patients received varying doses of trastuzumab and showed an overall 26% objective response rate, with higher rates among those with HER2 3+ overexpression compared to HER2 2+ expression. Clinical benefit rates were notably higher in patients with HER2 3+ overexpression. A substantial portion of patients with positive responses or clinical benefit did not experience disease progression even after 12 months. Frequently observed treatment-related adverse events included chills, fever, asthenia, nausea, and pain. Cardiac dysfunction manifested in 2% of patients with a cardiac disease history, and subsequent to trastuzumab discontinuation, further intervention was not required. The study demonstrated that trastuzumab as a monotherapy, exhibits efficacy and favorable tolerability as a first-line treatment for metastatic breast cancer, particularly in cases of HER2 3+ overexpression as determined by immunohistochemistry or gene amplification determined by fluorescence in situ hybridization analysis [175].

Bi-specific antibodies, such as bi-specific T cell engagers (BiTEs), have appeared as a promising avenue in cancer treatment due to their unique ability to simultaneously bind to two different proteins, guiding the immune system to target and attack tumors. By combining two distinct monoclonal antibodies, these constructs facilitate the connection between cancer cells and T cells, directing T cells to destroy cancerous cells via the CD3 and cancer antigen interaction. Dual-affinity re-targeting (DART) represents a bi-specific antibody molecule composed of variable heavy and light chain domains linked together, showcasing substantial potential in preclinical and clinical studies for cancer treatment [176, 177, 178]. Blinatumomab, the sole FDA-approved BiTE, has demonstrated significant clinical responses in B-lineage acute lymphoblastic leukemia by binding to CD19 on tumor cells and activating T cells via CD3. In a phase 3 trial for relapsed/refractory acute lymphoblastic leukemia (ALL), blinatumomab, an immunotherapy, displayed improved overall survival (OS) when compared to chemotherapy after initial treatment cycles. The study assessed additional blinatumomab cycles given as consolidation and maintenance therapy to patients in remission post-induction. Among those achieving remission, 32% received consolidation (cycles 3-5) and 13% maintenance (cycles $\ge$6). Patients on maintenance had longer median OS and relapse-free survival (RFS) than those without (median OS not reached vs 15.5 months; median RFS 14.5 months vs 9.8 months). Additionally, fewer adverse events occurred during maintenance (72.2%) versus induction (97.2%) and consolidation (86.1%). This highlights blinatumomab’s potential as a prolonged therapy, offering extended survival and manageable safety for relapsed/refractory ALL patients post-remission, without introducing new safety concerns. This trial was registered at https://www.clinicaltrials.gov/ as #NCT02013167 [179].

Bintrafusp alfa (M7824) is another investigated BiTE targeting both TGF-$\beta$ and PD-L1, with ongoing trials showcasing promising results in hematological malignancies [35, 176]. Combination therapy using BiTEs in conjunction with negative immune checkpoints like PD-1 and CTLA-4 has demonstrated safety and satisfactory antitumor responses, especially in advanced solid tumors [180]. However, despite their therapeutic potential, BiTEs carry a considerable risk of adverse effects, including CRS and neurologic complications, which necessitates careful monitoring and management during treatment [181]. Ongoing research aims to maximize the benefits of BiTEs while minimizing their associated risks to enhance their role in cancer therapy [35].

Oncolytic virotherapy (OV) is an innovative cancer treatment that employs viruses to target and destroy cancer cells while leaving healthy cells. This therapy employs modified viruses to infect and replicate specifically within tumor cells, ultimately causing their destruction. These viruses are engineered to selectively replicate within cancer cells, leading to their lysis or death, and triggering an immune response that helps in further eradicating the tumor [182].

The concept behind OV is based on the potential of certain viruses to preferentially infect and replicate in cancerous tissues due to specific mutations or alterations present only in tumor cells. Once the virus infects the cancer cell, it undergoes replication, resulting in the tumor cells destruction. This process generates antigens capable of stimulating the immune system, activating immune cells to identify and target any remaining cancer cells throughout the body. Several viruses, including adenoviruses, herpes simplex viruses (HSV), reoviruses, and vaccinia viruses, have been studied and engineered for oncolytic purposes. Advances in genetic engineering and molecular biology have enabled scientists to modify these viruses to enhance their specificity for cancer cells and to equip them with additional therapeutic genes, making them more effective in targeting tumors [183, 184, 185].

The clinical application of OV has shown promise in various types of cancers. Clinical trials investigating the safety and efficacy of OVs, both as standalone treatments and in combination with other therapies like chemotherapy or immunotherapy, have demonstrated encouraging results. Notably, the U.S. Food and Drug Administration (FDA) has approved OV for certain types of cancers, marking a significant advancement in the field of cancer treatment [186].

While OV holds immense potential, challenges remain, such as optimizing viral delivery to the tumor site, preventing premature immune clearance of the virus, and minimizing potential side effects. Additional research is being conducted to refine viral engineering, improve delivery methods, and identify optimal combinations with other cancer treatments to enhance its effectiveness [187].

Preclinical studies have shown the potential of OV, particularly with genetically engineered HSV-1 G207, in treating pediatric brain tumors. G207 is programmed to replicate only within tumor cells, leaving normal brain tissue alone. A case study evaluated the use of HSV-1 G207 in pediatric high-grade glioma, a condition known for poor survival rates and limited treatment options. The trial involved twelve children and adolescents with progressive or recurrent supratentorial brain tumors. Administered intratumorally, G207 showed an acceptable safety profile, with no severe adverse events attributed to treatment. Notably, G207 treatment led to neuropathological, radiographic, or clinical responses in most patients. Remarkably, the median overall survival (mOS) reached 12.2 months, with some patients surviving 18 months post-treatment. Equally significant was G207’s impact on TILs, significantly increasing their presence, transforming “cold” tumors into immunologically active ones. This case study suggests the potential of HSV-1 G207 in shifting the TME and improving outcomes in pediatric high-grade glioma (ClinicalTrials.gov number, NCT02457845) [188].

Talimogene laherparepvec (T-VEC) has gained approval for treating patients with recurrent melanoma. In a recent study, researchers explored the efficacy of T-VEC therapy in a cohort of 13 patients with primary cutaneous B-cell lymphoma (pCBCL). The findings were promising, with 11 patients exhibiting a positive response to T-VEC, including six complete responses. T-VEC showed notable efficacy in injected lesions, mirroring responses observed in melanoma. The study indicated that immune-mediated rejection might drive distant antitumor activity, as the virus was solely detected in injected lesions. Gene expression studies revealed rapid changes post-T-VEC treatment, indicating an increase in genes related to immune response. These results suggest T-VEC’s potential effectiveness in pCBCL, emphasizing the need for further research to define responses in non-injected lesions and understand oncolytic virus therapy better in cancer treatment [189].

In summary, OV represents a promising avenue in cancer treatment, leveraging viruses to selectively target and destroy cancer cells, while also stimulating the immune system for a comprehensive anti-tumor response. Continued research and clinical trials aim to further develop and refine this innovative therapeutic approach for improving outcomes in cancer patients.

Endogenous stimuli-responsive platforms are developed to respond the endogenous stimuli within the TME, such as hypoxia, pH, enzyme, or oxidative stress, and release therapeutic agents at the tumor site.

Tumor immunotherapy strategies are not always tumor precise. Few of these are also found in non-malignant tissues, and the unintentional release of tumor immunotherapeutic agents into the healthy tissues might have catastrophic effects. As a result, controlled delivery of tumor immunotherapeutic drugs into the precise location is crucial for producing effective antitumor immune responses while limiting adverse effects. Stimuli-responsive systems are built to allow for the desired release of loaded chemotherapeutics in a temporally and spatially controlled way [206].

The PTT is a potential alternative owing to its extreme low invasiveness and higher selectivity. It involves inserting the biomaterials which effectively convert the light energy (generally at near IR wavelengths) to heat inside the tumor tissue and illuminating them to enhance the tumor heating in a lethal manner [256]. As PTT depends on the long-wavelength light it does not harm the non-target tissue and irradiates the target tissue with the lesser energy [257, 258]. According to the clinical and preclinical reports, the hyperthermia in the tumor cells can improve the blood flow and can result in increased perfusion in the cancer tissue at time and temperature dependent manner. This alters the tumor permeability, oxygenation and decrease in the interstitial pressure, as well as resetting the normal physiological pH conditions. These changes could aid in the nanoparticle-based chemotherapy accumulation and distribution in the target tissue. There are proofs that have shown that the increased heat could help trigger the immune response by stimulating the immune cell activation (CD8⁺ T cells, NK cells and DCs) leading to the release of exosomes from the cancer cells and causing up-regulation in the inflammatory cytokine’s levels and heat shock proteins. Hyperthermia could lead to the induction of tumor cell necrosis or apoptosis releasing the antigens associated with the tumor which are occupied by the antigen Presenting cells thereby activating the immune system and inducing anticancer immune response [259, 260, 261, 262]. The recurrence of tumor after the use of single tumor targeting therapy is very high. Hence the combination of PTT and immunotherapy can lead to the inhibition of the tumor metastasis. One of the reports showed that the systemic delivery of tumor targeting PTT-based nanoagents by IVroute can result in the lower accumulation in the tumors. Hence, Chen et al. (2018) [263] investigated the potency and feasibility of intratumor administration in combination with immunotherapy without causing systemic toxicity by formulating polydopamine-coated Al₂O₃ nanoparticles with a higher PTT efficiency. These nanoparticles were synthesized by encapsulating Al₂O₃ nanoparticles with the biodegradable, non-toxic polydopamine demonstrating higher efficacy in PTT. The near IR radiation could potentially eradicate most target cancer cells, consequently inducing the release of TAAs. The combined presence of Al₂O₃ and cytosine-gunaine (CpG) serves as an adjuvant, eliciting a cell-mediated immune response that effectively eliminates residual cancer cells and diminishes tumor recurrence. The results indicated the usefulness of the combined PTT-immunotherapy for tumor shrinkage [263]. Zhang et al. (2019) [264] developed a gold nanoshell carrier for the photothermal gene release that target HER-2 and an immunologic adjuvant CpG sequence in the gastric cancer cells. This resulted in a multidimensional therapy including the immune, gene and PTT [264]. Chen & co-workers (2016) [265] developed a strategy for eliminating the primary tumors, impeding metastasis and stopping the tumor relapse by combining nanoparticle-based PTT with the immune checkpoint blockade (ICB) immunotherapy (Fig. 6A, Ref. [265]) wherein a photothermal agent ICG, and imiquimod (TLR7 agonist) co-encapsulated by PLGA. These multifunctional nanoparticles encapsulating NIR heaters and TLR agonists can be employed for photothermal tumor ablation thereby generating TAAs, which display vaccine-like responses which can be combined with the CTLA4 checkpoint blockade resulting in the highly efficient cancer immunotherapy (Fig. 6B) [265].

Tu et al. [266], introduced Ru1105, a self-assembled near-infrared light-activated ruthenium (II) metallacycle. Ru1105 synergistically potentiates immunomodulatory responses and reduces adverse effects in deep tumors through NIR-light excitation, ROS generation, selective tumor cell targeting, precision organelle localization and improved tumor penetration/retention capabilities. The structural and photophysical properties of Ru1105 were confirmed via UV-Vis spectroscopy and emission spectroscopy, showing suitable NIR absorption and emission properties for deep-tissue imaging and phototherapy, along with excellent stability and ROS capability. Ru1105 displayed superior cytotoxicity against various cancer cell lines (A549, HeLa, and HepG2), especially when combined with laser irradiation, attributed to ROS generation and photothermal effects. Mechanistic insights revealed Ru1105’s cellular uptake, subcellular localization, and induction of immunogenic cell death, validated through vaccination experiments in mice, activating CD8⁺ T cells and down-regulating Foxp3⁺ T cells, enhancing antitumor immune response and leading to significant tumor regression and improved survival in mice [266].

PTT could be used singally for direct eradication of the primary tumor or could be combined with the existing therapies to boost their efficacy. But the PTT-immunotherapy combination could enhance therapy for both primary as well as metastatic tumor cells at the distant sites and enhance anticancer efficacy with shorter duration.

Photodynamic therapy (PDT) is a treatment that uses light energy and a photosensitiser to eliminate cancer cells in a non-invasive manner [267]. Contrarily, immunotherapy improves the body’s immunological response to cancer cells. However, both therapies have their limitations when used separately. Combination therapies have been devised to overcome these drawbacks and increase their effectiveness in preventing cancer spread and recurrence. It has been demonstrated that combining PDT with immunotherapy improves the antitumor immune response by eradicating primary and distant cancers utilising various immunotherapeutic techniques, including immunological adjuvants, immune inhibitors, and ICB [268]. Recently, a treatment approach using a combination of therapies has shown promising results for treating cancers [269]. PDT is used to induce acute inflammation in cancer cells, attracting immune cells to the tumor site. It has the potential to cause immunogenic cell death, which releases signals of danger and pro-inflammatory cytokines as well as antigens specific to cancer. These signals cause the activation of T cells, DCs, and NK, which enhances the identification and elimination of cancer cells. Combining PDT with immunotherapy medications such as ICIs or cancer vaccines can boost the immune response [270]. PDT also changes the TME, encouraging immune cell infiltration and reversing the immunosuppressive properties of the tumor. A two-pronged attack on cancer cells is created when immunotherapy and PDT are combined, improving treatment outcomes, and raising the potential of prolonged remission [271].

A recent study looked at the possibility of immunotherapy as a beneficial treatment option when combined with PDT and chemodynamic therapy (CDT). While PDT and CDT both increase immunogenicity, their efficacy may be constrained by issues including hypoxia, low H₂O₂ activity, and excessive glutathione in the TME. Cu²⁺-Pyropheophorbide-a-Cysteine (CuPPaCC), a self-reinforcing compound that enables synergistic PDT/CDT while depleting glutathione, was created by researchers to overcome these constraints. These conjugates formed spherical nanoparticles that were then modified with hyaluronic acid (HA) forming HA modified Cu²⁺-Pyropheophorbide-a-Cystine conjugate (HSCuPPaCC) to facilitate tumor-specific targeting. They were encased in mesoporous silica and were found to exhibit a dual glutathione-depleting and ROS mechanism that elevated intracellular ROS levels, improved immunogenicity, effectively killed cancer cells, and boosted tumor sensitivity to checkpoint PD-L1 blocking therapy. Treatment with HSCuPPaCC in combination with anti-PD-L1 ICB therapy eliminated the primary tumor and completely suppressed the distant tumor in a CT26 mouse model. This study offers convincing support for the potential of PDT, CDT, and immunotherapy in combination as a novel therapeutic strategy for cancer treatment. The self-reinforcing conjugates showed effective tumor targeting, activation in the TME, and improved antitumor effects, underlining their potential as an effective approach for treating cancer [272].

Photo-mediated immunotherapy, which combines PTT and immunotherapy, has demonstrated potential in the treatment of cancer. However, its efficacy may be hampered by the immunosuppressive conditions found in malignancies. Fucoidan@Al(OH)₃-Poly(I:C)/IR-820, a nano-adjuvant that targets tumors, was created by researchers as a solution to this problem. This nano-adjuvant can release tumor antigens and has immunomodulatory properties that assist counteract immunosuppression and boost antitumor immunity. This multifunctional nanoadjuvant has been successfully used to treat breast cancer and prevent metastasis when combined with photothermal, photodynamic, and immunotherapy. This technique provides a potentially effective means of enhancing therapeutic effects and overcoming the difficulties associated with immunosuppressive TMEs in the management of breast cancer. This tumor-targeted nanoadjuvant has considerable potential because it may simultaneously release tumor antigen and modify the immune response [273].

ICB therapy has showed potential to treat advanced and metastatic cases of hepatocellular carcinoma (HCC). However, because of low exposure to tumor antigens and the TME’s strong immunosuppressive effects many HCC patients may not respond. To combat this, the Ce6@PMTKP light-triggered nanoplatform was developed, which combines chemo-photodynamic therapy with ICB therapy to increase its efficacy. The ROS-sensitive paclitaxel polymeric prodrug (PMTKP) for chemotherapy and Ce6 for photodynamic therapy were combined to create the Ce6@PMTKP micelles (Fig. 7A, Ref. [274]), which produced good tumor accumulation and light-triggered drug release (Fig. 7B). Combination therapy utilizing Ce6@PMTKP resulted in a considerable improvement in tumor removal, triggered immunogenic cell death, accelerated DC maturation, and increased the infiltration of CTL, which reduced the immunosuppressive effects of the TME (Fig. 7C).

The Ce6@PMTKP micelles completely regressed primary tumors when used in conjunction with anti-PD-L1 immunotherapy. They also successfully reduced distant metastatic tumors by boosting antitumor immune responses. The light-triggered nanoplatform shows promise for enhancing treatment outcomes and overcoming the difficulties associated with HCC, and this study supports the potential of combining chemo-photodynamic therapy with ICB therapy for HCC treatment [274].

William B. Coley revealed for the first time in 19th cent. that bacterial toxins may be utilized as immunotherapeutic agent to manage patients with ortho and soft tissue sarcoma. Cancer immunotherapy is revolutionizing to much greater extend. In 21st century, numerous investigations are carried out in the domain of oncology associated with immunology. Amalgamation of these therapies boosted the cancer treatment to the next level [275].

It basically targets the tumor cells through training the host human immune system such as lymphatic system. Immune therapy is known for its long-term memory for several foreign particles. The major disadvantages are this therapy is limited response rate to checkpoint blockers (CPB). Evidence suggests that only a minority of patients react to immune checkpoint blockers (CPBs) (usually 10–30% responses, conditional on the kind of cancer). Patients with cold tumors, which are characterised by a least number of immune cells or low activation of PD-L1, have a poor response to immune CPBs. In contrast, patients with hot tumors having a substantial number of tumor-passing immune cells and showing the expression of increased amounts of PD-L1 benefited from immune CPBs with durable medical results [276, 277].

Absence of antitumor immune response is a crucial factor that allows malignant cells to proliferate, disperse, and spread. PD-1, also known as CD279 and CD274, PD-L1, B7 homolog 1 (B7-H1) axis have a crucial role in the capacity of malignant cells to elude the immune system among the several immunological checkpoints identified over the last decade [278]. Blocking the link between PD-1/PD-L1 is critical for preventing cancer cells from bypassing anticancer immune responses. Currently, six monoclonal antibodies (mAbs) targeting PD-1 (Pembrolizumab, Nivolumab, Cemiplimab) [279] or PD-L1 (Avelumab, Atezolizumab, Durvalumab) [280] are used to treat certain solid tumors, and more than 15 other mAbs are in clinical development.

In the past decade, several researchers reported that chemotherapeutic agents have excellent antitumor activity, but also mentioned the resistance occurred in studies. The preclinical and human trails also explained the chemoresistance to several receptors that lead to fail of therapy. Likewise, a potent chemotherapeutic agent like doxorubicin, paclitaxel, mercaptopurine, cisplatin, hydroxyurea along with monoclonal antibodies reported for effective treatment in various carcinomas such as lung, brain, breast, and oral cancer and so on. In addition to eliminating cancer cells, they also induce systemic immune activation and immunogenic cell death [281, 282, 283].

Pancreatic ductal adenocarcinoma requires immediate development of innovative life-prolonging treatments (PDAC). Liu & colleagues (2021) [284] found that increased irinotecan administration via a mesoporous silica nanoparticle coated with lipid bilayer, commonly referred as a silicasome. ICD is characterized by the production of calreticulin and the release of HMGB1 in dying Kras-induced pancreatic cancer cells, as established by a vaccination experiment that inhibited Kras-induced pancreatic cancer (KPC) tumors development in the contralateral location. Strong antitumor immunity coexists with the enhanced irinotecan transportation through the silicasome and can be dynamically augmented by anti-PD-1 in the orthotopic paradigm. Beyond the deposition of perforin and granzyme B deposition, immunophenotyping validates the presence of calreticulin, PD-L1, HMGB1 and an autophagy marker. The silicasome induces a stronger chemo-immunotherapy response than the free or liposomal medication Onivyde. Relative to the administration of anti-PD-1 with either free irinotecan or Onivyde, the co-administration of silicasome and anti-PD-1 leads to a substantial improvement in overall survival [284]. Tarantino & colleagues (2021) [285] conducted human trails on 1496 TNBC patients and were observed. Results claimed that patients with high chances of relapse got improved pCR rates with low relapse. Platinum-based drugs such as cisplatin and carboplatin, and antibiotic agent anthracycline combination with anti-PD-L1 immunotherapeutic agents such as atezolizumab, pembrolizumab, durvalumab. Different trials were conducted with all combination of chemo- and immune-therapeutic agents with difference groups of TNBC patients of various stages (I–IV). The study claimed that use of PD-L1 agents significantly improve the risk of relapsing in TNBC patients. PD-L1 was also considered as a biomarker for disease detector in the early stages. The modification in the receptor can be easily useful in detection of stage of cancer [285]. Liu et al. (2021) [286] found that DOX and 5-carboxy-8-hydroxyquinoline (IOX1), a strong immunotherapeutic small drug, may inhibit tumors development in diverse animals. In vitro and in vivo, IOX1 reduces tumors PD-L1. It decreases multidrug resistance in cancer cells and enhances intracellular DOX accumulation, dramatically increasing DOX-induced ICD. IOX1 and DOX enhance T cell infiltration and activation while diminishing tumors immunosuppressive factors. Consequently, liposomal IOX1 and DOX eradicate several mouse cancer models, establishing enduring immunological memory against rechallenging subcutaneous (s.c.) and lung metastatic tumors. IOX1, a widely accessible antibody-free chemo-immunotherapy, treats cancer [286]. Similarly, FOLFOX, Dox and imiquimod, Docetaxel and IDO1 Inhibitor effectively used for the management of Colorectal and breast cancer [287, 288, 289, 290].

Zhu et al. [291], self-assembled the immunomodulator epigallocatechin gallate palmitate (PEGCG) and immunoadjuvant metformin (MET) into tumor-targeted micelles encapsulating doxorubicin (DOX)-loaded PEGCG-MET micelles (PMD) combined with immune checkpoint inhibitors (ICIs) for triple negative breast cancer. Therapy. PMD micelles efficiently delivered drugs with sustained release, targeting tumor cells via laminin receptors, inducing immunogenic cell death, releasing damage-associated molecular pattherns and activating DCs and T cells. Additionally, PMD micelles downregulated PD-L1 expression, enhancing antitumor immune response. In vivo, PMD micelles combined with anti-PD-1 efficiently inhibited tumor growth by activating CD8⁺ T cells and NK cells while reducing immunosuppressive cells, exhibiting prolonged circulation, tumor targeting and good biocompatibility, offering a promising strategy for TNBC therapy integrating chemotherapy and immunotherapy to enhance treatment efficacy [291]. Yu and colleagues [292] studied the strategy to elicit dual pyroptosis pathways using calcium sulfide-based nanoreservoirs for cancer immunotherapy. Neodymium (Nd3+)-doped calcium sulfide nanoparticles were coated with silica shell and conjugated with glucose oxidase to obtain multifunctional nanoreservoirs (CSSG). These nanoparticles demonstrated stability in biological environments stimulating TME. CSSG induced cell pyroptosis, inhibited tumor cell proliferation, triggered mitochondrial disfunction, elevated oxidative stress, and activated the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome pathway, leading to pyroptotic cell death. In vivo, CSSG exhibited potent antitumor effects, activating DCs and tumor-infiltrating T cells, stimulating immunostimulatory cytokine secretion and suppressing distant tumor growth, indicating its potential for inducing systematic antitumor responses and overcoming cancer metastasis [292].

New treatment strategies have been created in recent years for both orphan illnesses and the area of cancer. Moreover, the prognosis for certain advanced neoplastic illnesses has been significantly altered using CPBs, and the development of gene therapies has made it possible to treat conditions that were previously thought to be incurable [293]. ICIs reverse T cell fatigue, which is common in neoplastic illnesses, by blocking inhibitory receptors on the T cell membrane, thereby enhancing the antitumor immune response. Current ICIs target both the CTLA-4 and PD-1 or PD-L1 pathways, which play important roles in controlling autoimmunity. A monoclonal antibody targeting CTLA-4, such as ipilimumab, demonstrated improved overall survival in patients with metastatic melanoma who had undergone prior treatments over the past decade. Anti–PD-1 drugs (nivolumab, cemiplimab, and pembrolizumab) and anti–PD-L1 drugs (atezolizumab, avelumab and durvalumab) were utilized in a variety of solid and hematologic malignancies since 2015s. Although the use of CPBs dramatically increases patient survival in certain cancer types, such as lung cancer and melanoma, it may also produce immune-related adverse events (irAEs) owing to a lack in self-tolerance [294, 295].

The adoptive transfer of T cells modified with receptors has shown remarkable outcomes in the treatment of lymphomas and B-cell leukemias in patients. The result has inspired academic and corporate researchers to build comparable “off-the-shelf” receptors targeting common antigens on epithelial malignancies, the primary cause of cancer mortality. Use of this method to successfully treat the patients with solid tumors is unlikely to be easy. Due to the on-target identification of normal tissues, T cells engineered with receptors have the ability to induce lethal toxicity, and there is a scarcity of tumor-specific antigens that are common in tumor types [296]. Kamran et al. (2017) [297] demonstrated that myeloid mediated immunosuppression has enormous potential for improving the efficacy of gene therapy mediated immunotherapy for GBM. The data demonstrated that MDSCs comprise more than forty percent of the immune cells invading the tumors. These cells express chemicals that are essential for antigen-specific T cell suppression, including IL-4R, arginase, inducible nitric oxide synthase (iNOS), PD-L1, and CD80. Depletion of MDSCs significantly improved the thymidine kinase plus Fms-like tyrosine kinase ligand (TK/Flt3L) gene therapy-induced tumor-specific CD8⁺ T cell response, resulting in an improvement in median survival and the proportion of long-term survivors. In addition, adding CTLA-4 or PD-L1 immune checkpoint inhibition enhanced the effectiveness of TK/Flt3L gene therapy significantly [297]. Similarly, Chiocca and colleagues (2022) [298] reported that Veledimex (VDX)-regulatable IL-12 gene therapy induces tumor infiltration of CD8⁺ T cells in tumor, enhancing survival. However, it also upregulates immune checkpoint signaling, justifying a combination trial with ICIs in recurrent GBM. The results claimed that similar to IL-12 gene monotherapy, the toxicities of the combination were dose-related, predictable, and reversible when VDX and/or nivolumab dosages. Plasma pharmacokinetics of VDX indicated a dose-response association between VDX tissue penetration and IL-12 production. Serum IL-12 levels peaked in all participants around three days following surgery. The mOS for VDX 10 mg plus nivolumab was 16.9 months, whereas it was only 9.0 months for all participants [298].

Radiotherapy (RT) is an old therapy for the cancer treatment and has a significant impact in the treatment of tumor patients. According to the literature more than 60% of cancer patients accepted this technique [299]. The primary mechanism by which RT works is by eradicating cancer cells when their DNA is damaged (through apoptosis or autophagy, for example) during cell division or in between cell divisions (like in lymphocytes) [300]. Despite with these advantages of RT some drawbacks are also there. RT does not always eliminate the major tumor. This is particularly the case for diseases like pancreatic cancer. Radiotherapy can also cause a lot of toxicity to normal cells [301, 302]. To minimize this problem there is need for a new strategy. Recent research has shown that RT works because it causes the best immune reaction in the tissue that is treated. Experiments showed that mice without T and B cells needed a higher amount of radiation to get the same effect against tumors as mice with a healthy immune system [303]. Also, early research showed that RT was less effective in mice lacking NK, macrophages, or DC [304]. Also, it was shown that IFN-$\gamma$ was the main cytokine that turned CD8⁺ T cells into key effectors in response to RT [305]. Cancer immunotherapy has been regarded particularly an effective methods in oncologic medicine, especially in the treatment of solid tumors with ICIs [306]. Immune checkpoint inhibitor antibodies have changed the way that cancers like melanoma, NSCLC and renal cell carcinoma (RCC) are treated when they have spread. Some patients have had full reactions that have lasted for more than 5 years [307]. Immunotherapy has proven to be a successful oncologic therapy and combining it with RT can be an excellent strategy for treating cancer. Immunotherapies are cancer treatments that employs the immune system of the body to attack and destroy cancer cells. Many similarities exist between radiation therapies evolution and immunotherapies [308]. Thus, many ongoing clinical studies investigate whether radiation treatment and immunotherapy can work together for improved cancer treatment. Modern radiation treatment and immunotherapies are becoming more specialized, which has decreased their side effects and made them more useful in clinical cancer. Radiation and immunotherapy have gotten safer and better over time, which makes it possible for them to be used as part of combined-modality treatment methods. In 1970 first steel gives the concept of combining immunotherapy and radiotherapy which can increase the outcomes of the therapy. The Steel theory has been updated for the molecular age, with potential links between radiation and cancer medicines being highlighted. According to the new model, there are five ways in which radiotherapy and immunotherapy may operate together to enhance patient results. There is (1) coordination in space, (2) regulation in time, (3) collaboration in biology, (4) lethal increase, and (5) preservation of normal tissue [309]. Radiotherapy has both capability to immune activation and immune suppression, so the dose of radiotherapy and immunotherapy should be properly studied [310]. The following describes methods by which radiation may make tumor cells more dependent on immune-mediated death. These tumor cells that have been exposed to radiation upregulate components of negative feedback (such as checkpoint proteins), which can suppress the immunological response. Radiation can stimulate an immune reaction, but immunotherapy drugs that inhibit this feedback could revive it [311, 312].

Ukleja et al. (2021) [313] discussed about the treatment of genitourinary malignancies using immunotherapy and radiotherapy in combination. ICIs have been shown in preclinical and early clinical trials to have an additive impact with radiation treatment, increasing tumor cell death at both the local treated site and, in some instances, at remote sites via the abscopal effect. Author concluded based on previous data combination of both therapies may be solution for the problems of available treatment [313]. Lei et al. (2021) [314] discussed about the treatment of urological malignancy using combination therapy of radiotherapy and immunotherapy. It was observed that the radiation treatment and chemotherapy altogether improve the prognosis for various types of bladders tumors. Author discussed the interaction between radiation and immunotherapy for cancer was addressed, along with the impacts of radioactivity on the immune system [314]. Sezen et al. (2021) [315] addressed the difficulties that arise when planning immunotherapy clinical studies in conjunction with radiation treatment. Clinical trials begin with the formulation of a theory and establishment of primary study goals. Selecting a suitable theory that can be verified in future research and generating new questions for inquiry presents a challenge during the development of studies analysing mixtures of immunotherapy and radiation treatment (RT) [315]. De Felice et al. (2023) [316] describes the case report of NSCLC treatment using the combination of immunotherapy, radiotherapy, and denosumab.

Discovery of ICIs has been considered as a significant milestone in the arena of cancer therapy. ICIs have achieved tremendous positive therapeutic outcome in the different cancers like RCC, lung cancer, melanoma and CRC [317]. The checkpoint proteins for ICIs involve PD-L1/PD-1, LAG-3, CTLA-4, T cell immunoglobulin, mucin domain 3, and glucocorticoid stimulated tumor necrosis factor receptor associated proteins. In regular conditions, these molecules are properly expressed after the proper activation of immune system regulating the immune response. The adverse immune feedback generated from the cancer cells is utilized for generating the immunosuppressive microenvironment by causing over-expression of the immune checkpoint proteins like LAG-3 and PD-L1. Reports have indicated that PD-L1 is over-expressed in tumor and increases T lymphocytes apoptosis avoiding cancer cell recognition by the CTLs. Hence, anti-PD-L1/PD-1 is utilized to restore the steps in the immune response [317]. ICIs refer to the monoclonal antibodies which act by preventing this immunosuppression by inhibiting the involvement of these checkpoint molecules strengthening the immune response [319]. By inhibiting the immunosuppressive signals, the checkpoint inhibitors can improve body’s anticancer immune response [320].

The important immune checkpoints are PD-1, PD-L1 and CTLA-4. CTLA-4 is present on activated CD4⁺ and CD8⁺ T cells [320]. Firstly, Mak showed that the lack of CTLA-4 can lead to the accumulation of T cell blasts, indicating the negative impact on immune responses. In mice, CTLA-4 knockout mice have T cells which are super-activate and proliferating indicating that this receptor plays a role in T cell response regulation. This became the basis by which Allison depicted antitumor efficacy by blocking CTLA-4 [168]. During the initial T-cell stimulation, there is a competition of CTLA-4 with costimulatory receptor CD28 for binding with the ligands B7-1 and B7-2 present on the APCs. This is followed by the facilitation of the negative regulation of the immune response, suppressing the IL-2 secretion and T cell proliferation inhibiting the immune response to cancer cells. PD-1, a transmembrane protein present on the T cells and PD-L1, which may be expressed on T cells. The interaction between of PD-1 to PD-L1 diminishes the T cell responses to the TCR activation signals. As a consequence of the attenuation of antitumor T cell responses, the anticancer efficacy of antibodies inhibiting CTLA-4 and the PD-1/PD-L1 axis is observed [320]. To date, two anti-CTLA-4 antibodies tremelimumab antibodies ipilimumab are utilized for metastatic melanoma and mesothelioma, NSCLC respectively and three anti-PD-1 antibodies like Cemiplimab for skin carcinoma, nivolumab for melanoma, bladder cancer, NSCLC, RCC, HCC, Hodgkin lymphoma, stomach and oesophagus cancer; pidilizumab for follicular lymphoma, multiple myeloma, DLBCL, and pembrolizumab used for bladder cancer, NSCLC, melanoma, SCCHN, Hodgkin lymphoma, stomach and esophageal cancer, squamous cell carcinoma of skin. Three anti-PD-1 antibodies viz. (i) avelumab utilized in Merkel carcinoma, and metastatic urothelial cell carcinoma, (ii) durvalumab for urothelial bladder cancer, and (iii) atezolizumab for NSCLC and bladder. Ipilimumab has been employed widely for treating of numerous cancers like lung cancer, prostate, and kidney cancer. 20% patients with ipilimumab survived higher than 4 years and some survived for more than 10 years [320, 321]. With Nivolumab, the response rate for the treatment was more than 80% with Hodgkin’s lymphoma. The response for the PD-L1/PD-1 blocking antibody is more than 10%. The adverse effects of ICIs like rash, diarrhoea, colitis, endocrinopathies and hepatotoxicity. Fatal side effects are occasionally observed. The application of ICIs is constrained by elevated treatment-related toxicity and diminished response rates [5].

The FDA approved ICIs are illustrated in Table 1 [322, 323].

Cancer vaccine takes benefit of TAAs for stimulating the immune system, specially longer lasting and robust immune response of CD8⁺ T cells preventing the metastasis, growth, and recurrence of cancer cells. Cancer vaccines are divided in two categories: therapeutic and preventive. Preventive cancer vaccines prevent cancer occurrence by enhancing the immune response whereas therapeutic cancer vaccines eradicate cancer cells by inducing tumor specific immune reactions. In TVI, the TAAs are presented in the body of patient for enhancing the immune response to the tumors and activating the immune responses of the patient for inhibiting the tumor growth. TVI is used to mend the primary and secondary steps in immunotherapy antitumor response loop [317]. According to the reports, HPV-16 synthetic long peptide vaccine could re-establish normal vulvar neoplasia. Several vaccines have been prepared for preventing cervical carcinoma triggered by HPV infection. Tumor vaccines have been employed for preventing virus related recurrence of tumor as their impact in virus related cancers is not satisfactory. Till now, sipuleucel-T (Provenge) based immunotherapy stands as the sole FDA approved vaccine for prostate cancer, but it is found to show limited effects [317]. This vaccine can improve the survival of the prostate cancer patients by 3 months. Many experiments have shown that the cancer vaccines have shown great clinical effect.

Since a long time, the antigens utilized in the preparation of tumor vaccines were predominantly TAAs. Though these antigens can be present on the tumor cells, they can be also expressed in the normal cells [317]. Owing to the limited specificity for the tumor and immune tolerance, the autoimmune disorders like vitiligo take place. Recently antigens specific to tumor have been identified. For the identification of neoantigens, the cancer cells and the normal cells were taken from the patients followed by the sequencing of the relevant samples by transcriptome sequencing or whole exome sequencing for identification of nonsynonymous mutations existing in cancer cells. This is followed by the utilization of MHC peptide in combination with specific prediction algorithm for screening the antigen sequence that is most immunogenic for the personalized cancer vaccine preparation. Neoantigens possess high specificity as they emerge from the random mutations in the cancer tissues but not in the normal cells [325]. In the clinical trials, neoantigen (NA) based immunotherapies have shown better antitumor efficiency. Tumor mutation burden relates to the number of gene mutations in the cancer cells and indicates high correlation with the efficiency of NA based vaccines. Hence patients with TMB could be good candidates in case of NA based vaccine therapy. Patients with lesser TMB can be treated with TAA based vaccines. Hence, selecting the proper tumor antigens individually for patients could be a significant factor that determines the cancer vaccine success [325].

Cytokines refer to the molecular messengers allowing the immune system cells to connect to one another generating a robust, synchronized response for the target antigen. Cytokines are basically proteins, glycoproteins, or polypeptides with a molecular weight 30 KDa that transmit cell differentiation, proliferation anti-inflammatory or inflammation signals. There has been growing interest in exploiting the immune system for cancer eradication. The first cancer immunotherapy to be approved was cytokine immunotherapy. Several cytokines like IL-7, IL-12, IL-15, IL-18, IL-21, and GM-CSF have entered the clinical trials for the advanced cancer patients. To date. FDA approved anticancer agents include IL-2 for RCC and metastatic carcinoma and INF-$\alpha$ for stage III melanoma as an adjuvant therapy [317, 320, 326].

IL-2 is responsible for the activation, maturation, and viability of NK cells. Higher doses of IL-2 (HDIL-2) are responsible for anticancer activity and the low doses can enhance suppressor T cells proliferation suppressing the immune system activation and weakening the anticancer efficacy. Recently the treatments with other cytokines like IL-15 and IL-17 are in clinical trials. HDIL-2 was approved by FDA for the RCC treatment in 1992 and metastatic melanoma in 1998. GM-CSF is a cytokine that resembles IL-3, which stimulates IL-5 and myelopoiesis, the important growth factor for eosinophil by way of a common beta chain on the GM-CSF receptor. GM-CSF may induce initiation of T cells and maturation of DC for improving anticancer effect which has been utilized recently for granulocyte recovery. IFNs are utilized for promotion and maturation of macrophages, DCs, T lymphocytes and NK cells and regulates tumor blood vessel growth [317, 320, 326].

Adoptive cell transfer immunotherapy (ACT) is a personalized cancer treatment involving administration of immune cells with anticancer activity to the cancer patient. ACT has shown good anticancer efficiency, especially in haematological malignancies. The two main types of ACT are CARs and tumor-infiltrating lymphocyte (TIL) therapy. Both involve collection of immune cells from the patients, growing them in large amounts in the laboratory and the injection of these cells with immunologic functionality back into the patients or a new recipient host. In TIL therapy, tumor-specific T lymphocytes are isolated from the patient’s tumor followed by in vitro amplification and reactivation, and subsequently reintroduced into the patient. The use of this strategy is constrained due to its difficulty to obtain enough tumor-infiltrating T cells. In case of CAR-T cell therapy, the T lymphocytes are sourced from peripheral blood of patient and subsequently undergo in vitro transinfected with a CAR. After reinfusing in the patients, these cells exhibit the capability to selectively recognize tumor antigens, leading to the targeted destruction of cancer cells. The CAR-T cell treatment can maintain the activity for 10 years or more in vivo. Currently, CAR-T cell treatment is used for treating refractory large B-cell lymphoma and acute lymphoblastic leukemia.

Small molecule immunotherapy (SMI) is the utilization of small molecules for regulation of related enzyme activities or the receptors in the immune pathways for overcoming immunosuppression or for activation of antitumor responses. Small molecules medicines possess good tissue permeability, reasonable half-life, and good bioavailability. These small molecules include cyclooxygenase (COX-2) inhibitors, TGF-$\beta$ inhibitors, stimulator of IFN genes (STING) agonists, TLR agonists, retinoic acid-related orphan receptor gamma t (ROR$\gamma$t) agonists and indoleamine-2,3-dioxygenase (IDO) inhibitors [317, 327]. NG 919 is an IOD-1 inhibitor which selectively inhibits IDO-triggered T cell suppression and re-establishes a T cell response. NLG919 has a synergistic antitumor activity with PTT. COX-2 inhibitors block COX-2 enzymes which reduce prostaglandin production and decrease inflammation by inhibiting cytokines responsible for inflammation [317]. A TGF-$\beta$ inhibitor, could suppress TGF-$\beta$ induced immunosuppression. TLR agonists can stimulate APCs enhancing the vaccine immunogenicity [317]. STING protein is naturally present in the human body and could improve body’s immunity. It acts by inducing the IFN-$\beta$ production by tumor associated stromal cells and activates DCs, which leads to T cell priming and recruitment in the tumor environment. ROR$\gamma$t aids in the Th17 cells differentiation and IL-17 production which play a major role in the development of auto-immune diseases [317, 327].

Oncolytic immunotherapy uses OVs. These OVs are naturally occurring viruses administered via an IV or intralesional injections for inducing cell death in the cancer cells and activating the anticancer immune response [331]. OVs can result in tumor cell lysis and adaptive and innate immune response stimulation by selective replication in the cancer cells without causing any damage to the normal cells. This makes this type of immunotherapy superior compared to other immunotherapy approaches as it combats cancer without depending on the expression of a specific antigen [320]. USFDA approved OV include T-VEC, a genetically engineered oncolytic HSV for advanced melanoma. Most of the tumors are metastatic and hence an IVinjection is an important method of drug delivery to the tumors. Avoiding early removal of OVs because of the antiviral response becomes very essential. Ideal immunotherapy needs a balance between the antiviral and antitumoral responses. Various approaches have been tried for obtaining the balance and the therapeutic effect like the depleting antibodies, genetic modification, carrier cells and polymer coating [5]. Oncolysis when used in combination with immunostimulatory cytokines can improve the effect of OV therapy. OV therapy when combined with ICIs could increase the antitumor efficacy [184]. Intra-tumoral injection is safe and is preferred as it could prevent the humoral immunity from virus removal and repeated injections in the tumors can enhance strong immune response against the tumor [332]. OVs activate the immune system to identify the cancer cells and stimulate the anticancer immunity by enhancing immunogenicity and killing the cancer cells [320].