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 $\beta$-galactosidase (SA-$\beta$-Gal), and elevated expression of p16${}^{\text{Ink4a}}$. 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 senescence-associated secretory phenotype (SASP) [32, 33]. Cell senescence is a complex process involving multiple molecular pathways, including the TP53 and p16${}^{\text{Ink4a}}$/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].

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 affect 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.

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 incidence 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].

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${}^{\text{(waf1/cip1)}}$- and p16${}^{\text{Ink4a}}$-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${}^{\text{Ink4a}}$ [55]. interferon regulatory factor 8 (IRF8) inhibits AKT signalling and promotes the accumulation of p27${}^{\text{Kip1}}$ 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-1$\alpha$ [58], AKT [57], and nuclear factor kappa-B (NF-$\kappa$B) [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.

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-to-mesenchymal transition of neighbouring cells to promote tumour cell invasion [62].

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 promote 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.

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].

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.

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 ($\gamma$-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${}^{\text{Ink4a}}$, a senescence-associated 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].

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-$\alpha$ 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.

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′$\to$P5′ thio-phosphoramidate 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-2-ylca-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].