Cellular Senescence in Non-Small Cell Lung Cancer

Lung cancer has the highest mortality rate amongst all malignancies worldwide, and is the second-highest incidence of cancer in women. Non-small cell lung cancer (NSCLC) is responsible for approximately 80% of lung cancer cases. Recent studies indicate that cellular senescence may be a promising cancer biomarker. However, the regulation of cellular senescence and its underlying mechanisms in NSCLC are not yet fully understood. Here, we present a comprehensive analysis of the genes linked to cellular senescence in NSCLC. We also describe the secretory phenotype associated with NSCLC and examine its immune profile and prognostic potential. Our findings offer novel insights into the development of effective NSCLC treatments.


Introduction
Lung cancer is a particularly aggressive disease and is the leading cause of cancer-related mortality worldwide.There were approximately 2.2 million new cases of lung cancer in 2020 and 1.8 million deaths from this disease [1][2][3].Lung cancer is broadly classified into two categories based on the cell types involved, namely nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC) [4][5][6][7][8].NSCLC accounts for approximately 80% of cases and is characterized by the presence of anomalous cells that proliferate and metastasize rapidly, usually resulting in poor prognosis and limited therapeutic options [9,10].NSCLC can be further subdivided into three categories based on histological characteristics, namely adenocarcinoma, squamous cell carcinoma, and large cell carcinoma [11,12].Adenocarcinoma originates from mucusproducing cells in the respiratory tract lining and is the most frequently observed subtype, accounting for approximately 40% of NSCLC cases [13,14].Squamous cell carcinoma arises from the cells lining the air passages and accounts for 30% of NSCLC cases [15].Large cell carcinoma is a less frequent subtype, comprising around 1-3% of all primary lung cancers and usually originating from lung neuroendocrine cells [16].NSCLC is often asymptomatic during the early stages, thereby posing a challenge for early detection.Common symptoms such as coughing, chest pain, shortness of breath and weight loss are usually experienced at later stages [17].Smoking is the primary cause of NSCLC, with several other environmental factors also contributing to its development, including exposure to second-hand smoke and radon.Available treatments for NSCLC involve surgery, chemotherapy, radiation therapy, and targeted therapy [18,19].A better understanding of the molecular mechanisms underlying NSCLC is essential for the development of effective therapies that improve patient outcomes.Of note has been recent research on the involvement of cell senescence in NSCLC.
Senescence is a type of cellular aging and has been investigated as a potential biomarker for cancer [20].Senescent cells have been observed to accumulate in several cancer types, including NSCLC, and have been linked to tumour growth, resistance to therapy, and unfavourable patient outcomes.Despite these findings, the mechanisms that underlie cell aging in NSCLC remain incompletely understood, with more research needed to clarify the role of senescence in the development and progression of this disease.Senescent cells secrete various molecules that can induce inflammation, angiogenesis and tissue remodelling, thereby facilitating cancer progression.Although there is increasing awareness of the significance of cellular senescence in NSCLC, the factors that regulate this process in cancer cells remain poorly understood.Furthermore, the presence of senescent cells within NSCLC tissue has been linked to unfavourable prognosis and reduced patient survival rates [21].A better understanding of the role of cellular senescence in NSCLC could therefore have significant implications for the development of new therapies and for more accurate prediction of patient outcomes.It is also important to identify specific senescence markers of aging that could be used in the clinic.

Cellular Senescence and NSCLC
Cellular senescence is a biological phenomenon commonly referred to as cell aging and which exhibits multifaceted and intricate involvement in the progression of NSCLC [22].Some studies have reported that the onset of cell aging can impede NSCLC growth and potentially incite tumour regression.However, other studies have implicated senescent cells within the tumour microenvironment in the progression and metastasis of NSCLC [23,24].In addition, the presence of senescent cells in NSCLC has been correlated not only with the efficacy of treatments such as chemotherapy and radiotherapy, and also with resistance to these treatments [20,[24][25][26][27][28][29].

Definiton of Cell Senescence and Its Role in Cancer
Cell senescence is a state of irreversible growth arrest triggered by various stressors, such as DNA damage, telomere shortening, and oxidative stress [30].By studying inducible changes to the epigenome, Yang et al. [31] found that disruption of epigenetic information could lead to aging in mice.On the other hand, restoring the integrity of the epigenome could reverse the signs of aging, suggesting that loss of epigenetic information is a reversible cause of aging.The morphology and metabolism of senescent cells are different to those of normal cells.Senescent cells have a large and flattened cell morphology, increased expression of senescence-associated β-galactosidase (SAβ-Gal), and elevated expression of p16 Ink4a .These cells remain metabolically active but can no longer divide or proliferate [20].They secrete a range of inflammatory cytokines and other molecules in what is known as the senescenceassociated secretory phenotype (SASP) [32,33].Cell senescence is a complex process involving multiple molecular pathways, including the TP53 and p16 Ink4a /Rb pathways [34,35].These can be activated by various stressors, leading to the induction of cell senescence.While this is thought to limit the proliferation of potentially cancerous cells, recent evidence suggests senescent cells may also promote cancer by secreting SASP factors that stimulate inflammation and tumour growth.Researchers have sought to understand the role of cell senescence in NSCLC progression and therapy resistance [36].Accumulation of senescent cells in NSCLC may contribute to disease progression and therapy resistance [24].Exploiting senescence could therefore potentially be used to improve treatment outcomes [29,37,38].

Factors Regulating Cell Senescence in NSCLC
Several factors have been identified as key regulators of cell senescence in NSCLC.These encompass genetic alterations, epigenetic modifications, oxidative stress, inflammation, and the tumour microenvironment.For example, genetic alterations such as mutation of the TP53 tumour suppressor gene are known to promote cellular senescence in NSCLC cells [39,40].Epigenetic alterations such as DNA methylation and histone modifications can also af-fect the regulation of cell senescence in NSCLC [41,42].Furthermore, exposure to environmental toxins such as cigarette smoke can result in oxidative stress, which can in turn induce cell senescence in NSCLC [43].Inflammation has also been linked to cellular senescence in NSCLC, with pro-inflammatory cytokines such as the chemokine (C-X-C motif) receptor 2 playing a role [44].Lastly, cell senescence in NSCLC can also be regulated by the tumour microenvironment, which encompasses interactions between cancer cells and stromal cells [24].The matricellular protein cellular communication network factor 1 (CCN1)/cysteine-rich 61 (CYR61) suppresses NSCLC cell growth by inducing senescence [45].
Regulation of cell senescence in NSCLC is a multifaceted phenomenon that can be influenced by various factors.Comprehensive elucidation of the underlying mechanisms that regulate cell senescence in NSCLC, as well as the identification of effective therapeutic interventions that target this process remain active areas of research.Indeed, further investigations are warranted to gain a deeper understanding of the complexities of this process and to develop potentially novel therapeutic avenues.

Genes Associated with Cell Aging in NSCLC
The process of cell aging is multifaceted and involves modifications in gene expression and activity.Multiple genes have been found to exert regulatory effects on cell aging in NSCLC.Elucidation of the molecular mechanisms and identification of the relevant genes that underlie the regulation of cell aging in NSCLC may provide valuable insights into the pathophysiology of this disease and could inform the development of novel therapeutics.Such findings may have implications for the optimization of therapeutic strategies against NSCLC.

Genetic Mutations and Alterations in NSCLC
NSCLC is a highly heterogeneous disease with a diverse array of genetic mutations and alterations that contribute to its pathogenesis and progression.Among the most frequently mutated genes in NSCLC are TP53, KRAS, EGFR and ALK [46].Aberrations to these genes can alter the normal signalling pathways, enhance cell proliferation, and increase resistance to chemotherapy and targeted therapies.The tumour suppressor gene TP53 plays a critical role in regulating cell cycle arrest and apoptosis in response to DNA damage.TP53 mutations are present in approximately 50% of NSCLC cases and are associated with poor prognosis and resistance to chemotherapy [47].Mutations in KRAS are found in approximately 15-25% of NSCLC cases and activate downstream signalling pathways, leading to cell proliferation and survival.KRAS mutations are associated with resistance to targeted therapies and poor prognosis [48].EGFR mutations are found in approximately 10-15% of NSCLC cases, with a higher inci-dence reported in non-smokers and Asians [49].These mutations activate downstream signalling pathways that result in cell proliferation and survival.EGFR mutations are associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and improved prognosis [50].ALK rearrangements are found in approximately 5-6% of NSCLC cases and activate downstream signalling pathways that lead to cell proliferation and survival.ALK rearrangements are associated with sensitivity to ALK inhibitors and improved prognosis [51].Other genetic mutations and alterations in BRAF, HER2, MET, RET, and ROS1 also contribute to NSCLC pathogenesis and may be targets for novel therapies [52].

Specific Genes and Pathways Implicated in Cell Aging in NSCLC
Several genes and pathways have been identified as crucial regulators of cell aging in NSCLC.Aberrant regulation of these genes and pathways has been implicated in the development and progression of NSCLC.Understanding their mechanism of action is therefore critical in the development of new therapeutic strategies for this disease.The tumour suppressor gene TP53 plays a vital role in regulating cell cycle progression and apoptosis [53].TP53 mutations are frequently observed in NSCLC and are associated with increased cellular proliferation, decreased apoptosis, and resistance to chemotherapy, all of which contribute to tumorigenesis [54].Oncogene-induced senescence is a tumour-suppressing defence mechanism [55].Activation of the ubiquitin-specific proteases 5 (USP5)-Beclin-1 axis is pivotal for overcoming intrinsic TP53-dependent senescence in KRAS-driven NSCLC development [40].The matricellular protein CCN1 suppresses NSCLC cell growth by inducing senescence through the TP53/p21 pathway [45].Short-carbon chain C (2)-ceramide can effectively sensitize paclitaxel(PTX)-induced senescence of NSCLC cells via both p21 (waf1/cip1) -and p16 Ink4a -independent pathways [56].Specific gene expression changes also occur during cellular aging in NSCLC.For example, myeloid zinc finger 1 mediates oncogene-induced senescence by promoting the transcription of p16 Ink4a [55].interferon regulatory factor 8 (IRF8) inhibits AKT signalling and promotes the accumulation of p27 Kip1 protein, resulting in the senescence of NSCLC cells [57].Homeodomain-only protein homeobox (HOPX) acts as a tumour suppressor in various cancer types.Forced expression of HOPX enhances cellular senescence by activating oncogenic Ras and the downstream mitogen-activated protein kinase (MAPK) pathway in NSCLC [42].Several other signalling pathways, including c-Myc/HIF-1α [58], AKT [57], and nuclear factor kappa-B (NF-κB) [59] have also been implicated in cellular aging and NSCLC progression.However, further research is needed to fully elucidate the mechanisms by which these genes and pathways contribute to cellular senescence in NSCLC.

Secretory Phenotypes Associated with Cell Aging in NSCLC
Cellular senescence is a multifaceted process that involves not only the cessation of cellular proliferation, but also the acquisition of a SASP.This phenotype is marked by the release of various cytokines, chemokines and growth factors, and is known to exert a pivotal role in tissue regeneration.In the context of malignant transformation, the SASP has been linked to cancer progression, immune subversion, and metastatic dissemination.Therefore, understanding the intricate interplay between cellular senescence and the SASP is of paramount importance for devising novel therapeutic strategies that target age-related disorders and cancer.

SASP and Its Role in Cancer
The SASP is a characteristic hallmark of senescent cells, as well as being present in cancer cells.This phenotype is characterized by the secretion of a diverse array of cytokines, chemokines and growth factors with varied effects on tumorigenesis.SASP is a double-edged sword.On one hand, early SASP is involved in numerous biological processes such as wound healing, immune surveillance, and tissue regeneration.On the other hand, the prolonged existence of SASP can reshape the tumour microenvironment by causing chronic inflammation and thus promoting tumour progression.This can lead to increased tumour vascularisation [60], the promotion of tumour cell migration and metastasis [61], and the induction of epithelial-tomesenchymal transition of neighbouring cells to promote tumour cell invasion [62].

Specific SASP Factors Associated with NSCLC
Several specific SASP factors in NSCLC have been reported to play important roles in inducing angiogenesis, invasion, and metastasis [61,63].The Interleukin-6 (IL-6) cytokine level is increased in the serum of NSCLC patients and is associated with poor prognosis [64,65].IL-6 promotes the proliferation, migration and invasion of NSCLC cells through activation of the STAT3 signalling pathway.It also inhibits apoptosis and enhances resistance to chemotherapy and radiotherapy.IL-6 has also been shown to induce the expression of angiogenic factors such as VEGF, which promote the formation of new blood vessels and facilitate tumour growth [66].Interleukin-8 (IL-8) is another cytokine that is frequently upregulated in NSCLC and has also been linked to tumour progression and metastasis [67].It promotes the proliferation, migration and invasion of NSCLC cells by activating the AKT and extracellular regulated protein kinases signalling pathways [68].Other SASP factors that have been associated with NSCLC include matrix metalloproteinases (MMPs) such as MMP-3 and MMP-9, which are involved in extracellular matrix remodelling and tumour invasion [69].In addition, chemokines such as Chemokine (C-C motif) ligand 2 pro-mote the recruitment and polarization of tumour-associated macrophages and eliminate senescent cells, thereby inhibiting cell carcinogenesis [70].In summary, specific SASP factors play important roles in the development and progression of NSCLC by promoting cell proliferation, migration and invasion, by enhancing angiogenesis and immune suppression, and by contributing to chemotherapy and radiotherapy resistance.

Immune Profile and Prognosis of Cell Aging in NSCLC
Immune cells play a critical role in the progression of NSCLC.The immune profile of NSCLC can be influenced by cellular senescence, which has been found to affect prognosis.Recent research suggests that senescent cells in NSCLC stimulate the recruitment of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) into the tumour microenvironment, resulting in immune suppression and tumour progression.Furthermore, these senescent cells release cytokines and chemokines that not only further repress the immune response, but also promote tumour growth [61].Senescent cells in NSCLC may facilitate the development of an inflammatory microenvironment marked by elevated levels of cytokines such as IL-6 and IL-8, which may further contribute to tumour growth and metastasis [44].
A recent study reported that the poor prognosis of NSCLC was associated with the presence of senescent cells, since these correlated with worse overall patient survival [71].Senescent cell targeting in a mouse model of NSCLC resulted in a decrease in MDSCs and Tregs in the tumour microenvironment and an increase in effector T cells, leading to reduced tumour growth and improved survival [72].Therefore, the presence of senescent cells and their secretory phenotype may be closely linked to the immune profile and prognosis of NSCLC.Hence, the targeting of senescent cells and their SASP may be a promising strategy to improve the immune profile and prognosis of NSCLC.The potential for precision oncology in NSCLC is suggested by the underlying mechanism for treatment.
NSCLC is characterized by a complex interplay of genetic alterations, cell differentiation hierarchies, epigenetic modifications, microenvironmental factors, and tumour heterogeneity.The intricate microenvironment is comprised of a diverse population of tumour cells and immune cells, including macrophages, vascular endothelial cells, MDSCs, dendritic cells (DCs), natural killer (NK) cells, and various subtypes of T cells, all of which contribute to a highly heterogeneous niche.Consequently, treatment strategies for NSCLC must take into account the multifaceted nature of this disease, which requires a comprehensive understanding of the interactions between tumour and immune cells within the tumour microenvironment.Further research is needed to identify novel targets and to develop innovative therapies that can modulate the intricate network of signalling pathways and immunological responses in NSCLC, thereby resulting in improved patient outcomes.

Involvement of the Immune System in NSCLC
NSCLC is known for its capacity to evade the immune system, proliferate, and metastasize throughout the body.Although the immune system has a crucial role in identifying and eliminating malignant cells, NSCLC cells have the ability to evade immune recognition by employing various strategies such as reducing antigen presentation, increasing the expression of immunosuppressive molecules, and recruiting immunosuppressive cells.These evasion mechanisms are believed to contribute to the resistance of NSCLC to immune-based therapies [73].
There has been increasing interest in the use of immunotherapies, such as immune checkpoint inhibitors, to activate the immune system and thus improve the outcome of NSCLC patients [74,75].Several studies have shown that immunotherapy can improve the survival of NSCLC patients with specific biomarkers, such as high expression of programmed death-ligand 1 (PD-L1), or high tumour mutational burden (TMB) [76].The relationship between cell aging and immune infiltration in NSCLC has also been investigated [37].Senescent cells in NSCLC can promote immune evasion and reduce T cell infiltration in the tumour microenvironment through the production of SASP factors, such as IL-6 and IL-8 [77].Other studies have shown that the immune system may play a role in clearing senescent cells from tissues, suggesting that it may also regulate cell aging in NSCLC [37].Therefore, a better understanding of the immune profile of NSCLC and its relationship to cell aging could provide important insights for the development of immunotherapies and personalized treatment strategies in NSCLC patients [21,78].

Effects of Cell Aging on Immune Response in NSCLC
Cell aging has been shown to have a significant impact on the immune response in NSCLC.SASP factors, including IL-6 and IL-8, are known to create an inflammatory microenvironment within the tumour, leading to immune suppression and the escape of cancer cells from immune surveillance [79].Cell aging can also cause changes in the tumour microenvironment that promote cancer cell growth and suppress immune function [80].Several studies have indicated that the presence of SASP factors in NSCLC is linked to reduced infiltration of immune cells such as T cells and natural killer cells into the tumour microenvironment.Furthermore, SASP factors can induce the accumulation of immunosuppressive cells, including regulatory T cells and MDSCs, which inhibit immune function [77].Additionally, cell aging can alter the expression of immune checkpoint proteins, such as programmed cell death protein 1 (PD-1) and PD-L1, thereby inhibiting T cell function [81,82].Elevated expression of PD-L1 in NSCLC has been associated with a worse prognosis and reduced response to immunotherapy [83].Understanding the effects of cell aging on the immune response in NSCLC is therefore, critical for the development of more effective treatment strategies.

Prognostic Implications of Cell Aging in NSCLC
Emerging evidence suggests the SASP and cell aging may have prognostic value in NSCLC.Indeed, certain SASP factors have been identified as potential biomarkers for poor prognosis in NSCLC patients.Elevated serum levels of IL-6 and IL-8 have for example been linked to reduced overall survival of NSCLC patients [84].Several studies have also reported that high levels of SASP factors such as IL-6, IL-8, and matrix metalloproteinase-9 (MMP-9) are associated with the poor prognosis and survival of NSCLC patients, while preclinical studies have shown that SASP factors can promote tumour growth and metastasis.Combining these biomarkers with traditional prognostic factors was found to improve the accuracy for predicting patient survival.Furthermore, elevated levels of the SASP factor plasminogen activator inhibitor-1 (PAI-1) have been associated with worse progression-free survival and overall survival of NSCLC patients [85].These findings highlight the potential utility of SASP factors as predictive biomarkers for NSCLC prognosis and treatment response.However, further research is needed to validate these findings and to identify additional SASP factors with prognostic value in NSCLC.
Specific biomarkers linked to cellular senescence could also serve as valuable predictive tools for therapeutic efficacy in NSCLC patients.Notably, it was reported that elevated levels of histone H2AX phosphorylation (γ-H2AX), a marker for DNA damage, could predict good response to chemotherapy and the survival of NSCLC patients [86].Another study found that a tumour senescence signature with high expression of p16 Ink4a , a senescenceassociated protein, had significant prognostic value for the overall survival of NSCLC patients [71].Several methods and biomarkers are currently available for the detection of cellular senescence and for the prediction of patient outcome.However, due to differences at the translational level and the lack of gold standard biomarkers, there is an urgent need for uniform and consistent biomarkers of cellular senescence [37].

Potential Targets for NSCLC Treatment Based on Cell Aging Mechanisms
Recent advances in our understanding of cell aging mechanisms in NSCLC have led to the identification of potential targets for treatment.One approach is to develop drugs that target specific pathways involved in cell aging, such as the TP53 pathway or the telomerase pathway [87].There are currently several ongoing clinical trials in NSCLC patients with TP53 mutations that target the TP53 pathway, including PRIMA-1 and APR-246.Another approach currently in the preclinical research phase is to target SASP factors using anti-IL-6 and anti-IL-8 antibodies [88,89].Using a KRAS-mutant mouse model of lung cancer, a combination of MAPK and cyclin-dependent kinase 4/6 inhibitors was found to promote NK cell surveillance by activating SASP components (tumour necrosis factor-α and intercellular adhesion molecule-1), leading to tumour cell death [90].
The identification of predictive biomarkers for treatment response based on cell aging mechanisms is currently also an active area of research.For example, the expression level of specific SASP factors or the presence of certain genetic mutations may be accurate predictive biomarkers for the response to treatment of drugs that target these pathways [91].The development of targeted therapies based on cell aging mechanisms therefore holds promise for improving the treatment outcomes of NSCLC patients [37].However, further research is needed to validate these targets and biomarkers, and to test the safety and efficacy of the targeted drugs in clinical trials.

Current and Emerging Therapies That Target Cell Aging in NSCLC
Recent studies have highlighted the potential of targeting cell aging mechanisms as a novel strategy for NSCLC treatment.Several drugs that target specific pathways involved in cell aging have shown promising results in preclinical and clinical studies.Of note, senolytics are a class of drug that selectively target senescent cells and induce their apoptosis.The senolytic drugs dasatinib [92] and quercetin [93] have shown promising results in preclinical studies of NSCLC [94].Telomerase inhibitors such as imetelstat and lipid-modified N3′→P5′ thiophosphoramidate oligonucleotide (GRN163L) were found to inhibit the growth of NSCLC cells in preclinical studies [95].Wang et al. [96] reported that bortezomib induced cellular senescence of A549 lung cancer cells by inducing telomere shortening.The mammalian target of rapamycin (mTOR) pathway has also been implicated in the regulation of cell senescence.In preclinical studies, the mTOR inhibitors rapamycin and everolimus were found to induce senescence and inhibit the growth of NSCLC cells [97][98][99].Another study reported that the anti-proliferative small molecule ethyl(2-methyl-3-((E)-((naphtha(2,1-b)furan-2ylca-rbonyl)hydrazono)methyl)-1H-indole-1-yl)acetate) (STK899704) promoted cell death by inducing DNA damage response pathways and senescence after cell cycle arrest [53].CBP/p300 histone acetyltransferases (HAT) are critical transcription coactivators involved in multiple cellular activities.They appear to act at multiple levels in NSCLC and may therefore represent promising druggable targets.Pharmacological targeting of CBP/p300 drives a redox/autophagy axis that leads to senescence-induced growth arrest in NSCLC cells [100].Immune checkpoint inhibitors such as pembrolizumab and nivolumab have also shown promising results for the treatment of NSCLC, particularly in patients with high levels of PD-L1 expression [101].The targeting of SASP factors such as IL-6 and IL-8 may also enhance the response to immunotherapy.Other targeted therapies that have been investigated in the context of NSCLC and cell aging include Cyclin-dependent kinase (CDK) 4/6 pathway inhibitors, Heat Shock Protein (HSP) 90 inhibitors, and histone deacetylase (HDAC) inhibitors [102].Furthermore, "one-two punch" sequential treatment provides a therapeutic option to reduce the risk of tumour progression and avoid adverse reactions by eliminating senescent cells induced by conventional anti-cancer treatments such as radiotherapy/chemotherapy [37].

Discussion and Conclusion
Lung cancer remains a major contributor to cancerrelated mortality worldwide, with NSCLC being the most prevalent subtype.Recently, there has been growing research interest on the role of cellular senescence in the pathogenesis and progression of NSCLC.This comprehensive analysis covers the multiple facets of cellular senescence in NSCLC, including the relevant genes and signalling pathways, secretory phenotypes, immune characteristics, and therapeutic implications.
Cellular senescence is a biological process characterized by the irreversible growth arrest of cells due to diverse cellular stressors [103].This process has emerged as a potentially useful prognostic and predictive biomarker for cancer, including NSCLC.Numerous genes and pathways have been implicated in cellular senescence in NSCLC, including TP53, CDKN2A and telomerase.TP53, also referred to as the "guardian of the genome", plays a pivotal role in DNA damage response and is frequently mutated in NSCLC.CDKN2A is another tumour suppressor gene that regulates the cell cycle and is frequently inactivated in NSCLC.Telomerase maintains telomere length and prevents genomic instability.It is frequently reactivated in cancer cells, including NSCLC.In addition to the presence of genetic alterations, cellular senescence in NSCLC is associated with the secretion of several pro-inflammatory and pro-tumorigenic factors, collectively known as the SASP.These include a range of cytokines, chemokines, growth factors, and extracellular matrix proteins.Various SASP factors, including IL-6 and IL-8, have been associated with unfavourable prognosis in NSCLC patients.
The pivotal role of the immune system in the development and progression of NSCLC is well established.Emerging evidence now indicates that cell aging can modulate the immune response in NSCLC.Specifically, senescent cells have been shown to promote the infiltration of immunosuppressive cells, including MDSCs and regulatory T cells, into the NSCLC tumour microenvironment, leading to immune evasion and resistance to immunotherapy.How-ever, the induction of senescence has also been reported to enhance the anti-tumour immune response and to improve the efficacy of immunotherapy in NSCLC.Accordingly, the targeting of cell aging in NSCLC represents a promising therapeutic strategy for improving treatment outcomes.Several potential targets have already been identified and include SASP components and the immune system.Notably, inhibition of the SASP factors IL-6 and IL-8 has been found to suppress tumour growth in preclinical models of NSCLC.Immune checkpoint inhibitors that target negative regulators of the immune response have also shown promise in the treatment of NSCLC, especially when combined with senolytic drugs that selectively eliminate senescent cells.
Cell aging is a multifaceted and intricate phenomenon during the development and progression of NSCLC.The involvement of specific genes and pathways, SASP factors and immune factors are all promising areas for further research aimed at improving NSCLC treatment.Future studies should therefore strive to increase knowledge of the underlying mechanisms responsible for cell aging in NSCLC, and to identify and validate robust biomarkers for predicting treatment response.This should allow for the development of more effective strategies that target cell aging in the clinical setting.
Natural Science Foundation, Grant number 2023J316; Medical Scientific Research Foundation of Zhejiang Province, Grant number 2022KY1138; Science and technology innovation guidance fund project of Hangzhou Medical College, Grant number CX2022006; HwaMei Reasearch Foundation of Ningbo No.2 Hospital, Grant number 2022HMKY37; HwaMei Reasearch Foundation of Ningbo No.2 Hospital, Grant number 2023HMKY20; HwaMei Reasearch Foundation of Ningbo No.2 Hospital, Grant number 2023HMKY32; Ningbo Top Medical and