2.1 Cellular senescence and mitochondrial metabolism

Mitochondria play an essential role in the most fundamental intracellular energy conversion processes. Severe impairment of normal cellular energy conversion processes can result from mitochondrial dysfunction, particularly in tissues that significantly depend on mitochondria for chemical energy production [34]. Interestingly, dynamic changes in the TME may complete the regulation of metabolic reprogramming through altering the composition of mitochondrial oxidative phosphorylation complexes and generating excess reactive metabolic by-products. These effects ultimately induce mitochondrial dysfunction and age-related metabolic disorders (including tumor development) [35]. Notably, inefficient adenosine triphosphate (ATP) production is a characteristic of senescent cells. An increase in the adenosine monophosphate/ATP (AMP/ATP) ratio results in a bioenergetic imbalance. This decreased ATP production can be explained by lower oxygen phosphorus efficiency associated with a decrease in mitochondrial membrane potential [36]. Senescent cells mediate an increase in tricarboxylic acid cycle metabolites that play multiple roles in the microenvironment, including lymphangiogenesis, induction of stem cell function, immune regulation, tumorigenesis, DNA methylation, and post-translational protein modifications [37, 38]. Given that senescence is characterized by epigenetic and chromatin modifications, the regulation of these metabolites may have an impact on the senescence phenotype.

Human fibroblast senescence-induced increases in AMP/ATP and adenosine diphosphate/ATP (ADP/ATP) ratios promote activation of AMP-activated protein kinase (AMPK), a key mediator of cellular metabolism, resulting in phosphorylation and activation of p53 [17]. Downregulation of proliferative genes, such as cell cycle protein A, or reduced phosphorylation of retinoblastoma proteins are strongly associated with metabolic programming and senescence. Importantly, AMPK activation can enhance p16 expression by increasing the nuclear presence of the RNA-stabilizing factor human antigen R protein and suppressing the stability of mRNAs encoding cell cycle proteins, leading to a senescent phenotype. This mitochondrial dysfunction-induced senescence phenotype potentially supports tumor progression. For example, earlier studies have reported that aberrant glycolytic flux and T cell depletion caused by mitochondrial defects exacerbate liver cancer [39]. In addition, mitochondrial dysfunction in senescent fibroblasts has been shown to downregulate transient receptor potential cation channel subfamily C member 3 (TRPC3) expression and induce cellular senescence, resulting in the secretion of pro-inflammatory and pro-tumor molecules (such as IL-8, epithelial-derived neutrophil-activating peptide 78 (ENA-78), and growth-related oncogene-alpha (GRO-α)) through SASP acquisition that promote tumor epithelial cell proliferation and prostate cancer growth in vivo [40]. Accordingly, the intrinsic link between mitochondrial dysfunction and senescence contributes to the formation of an immunosuppressive microenvironment and tumor proliferation. Given the significant correlations among senescence, tumors, and inflammation, elucidation of their functions and underlying mechanisms may aid in the identification of novel therapeutic approaches for combating senescence and age-related diseases. DNA damage and epigenetic modifications, both of which are hallmarks of senescence, also have the potential to induce mitochondrial dysfunction. For instance, chronic DNA damage is reported to mediate mitochondrial dysfunction and the development of radiotherapy-resistant glioblastoma [41]. Furthermore, m⁶A methylation modifications induce mitochondrial dysfunction that affects the metabolic reprogramming of cancer cells, which, in turn, increases cell proliferation, tumor initiation, and metastasis [42]. Similarly, primary tumor senescence can accelerate cancer metastasis via EVs. Specifically, breast cancer senescence-mediated metabolic reprogramming is induced by activating cancer-associated fibroblasts (CAFs) through the release of metabolites (e.g., methylmalonic acid) and promoting the release of IL-6-loaded EVs secreted by bovine milk to accelerate metastatic progression of lung cancer [43, 44]. Based on the collective findings, it is hypothesized that during cell senescence, multiple features (including epigenetic modifications, SASP, and intercellular communication changes) regulate mitochondrial function and mediate the reprogramming of energy metabolism or immune cell phenotypes, consequently favoring tumorigenesis and progression in multiple dimensions. Tumor proliferation, in turn, accelerates the accumulation of DNA damage and epigenetic alterations, and induces mitochondrial dysfunction that leads to complete metabolic reprogramming. Through this process, a tumor-friendly milieu is continuously generated, mediating a vicious microenvironmental cycle that lasts until nutrient depletion.

The existing literature clearly demonstrates that senescent cells exhibit significant alterations in mitochondrial function and metabolism. However, many of the reported observations are limited to relatively small cell populations and may not apply to all subtypes of senescent cells. Indeed, mitochondrial and metabolic parameters are reported to vary depending on the types of senescent cells and stressors. Although evidence of mitochondrial dysfunction in senescent cells cultured in vitro is available, our understanding of the altered mitochondrial function in senescent cells in tissues in vivo is currently limited. Further in-depth characterization of mitochondrial function in different types of senescent cells is warranted.

2.2 Cellular senescence and glucose metabolism

Abnormal sugar metabolism is a feature of tumor metabolic reprogramming. Increased glycolytic activity and lactate fermentation are the primary energy metabolic features associated with high invasiveness of tumor cells [45]. Oxygen consumption is additionally necessary for tumor proliferation and, occasionally, the demands of tumors cannot be met due to low oxygen concentrations. In such cases, tumor cells adjust to these situations by performing adaptive changes to meet their increased bioenergetic and biosynthetic needs through multiple metabolic pathways [46]. Fibroblast senescence is linked to several systems that regulate the microenvironment. These pathways induce mitochondrial dysfunction and increase glycolysis, thereby causing a shift in the energy production from mitochondria to glycolytic sources [47]. The adaptive metabolic alterations contribute to a hypoxic and acidic TME and support tumor proliferation through multiple pathways. In a similar manner to aerobic glycolysis, senescent chondrocytes alter their metabolism, accompanied by a lower energy state and increased AMP/ATP ratio. This process may further accelerate the induction of senescence [48]. Pyruvate, a key metabolite at the intersection of glycolysis and mitochondrial respiration, plays a crucial role in the metabolism of senescent cells [49]. Synthesis of pyruvate during glycolysis requires the reduction of nicotinamide adenine dinucleotide (NAD⁺) to NADH. Lactate dehydrogenase can replenish the NAD⁺ pool [50] by converting pyruvate and NAD⁺ into lactate, which accumulates outside senescent osteosarcoma cells to form an acidic TME in some cases.

The dual nature of cellular senescence (tumor promotion and suppression) creates an apparent contradiction between senescence promotion and tumor evolution. In fact, senescence regulates metabolic reprogramming, creating an environment conducive to tumor growth (including SASP and immunophenotypic suppression). When tumor growth exceeds the rate of senescence-mediated apoptosis, the malignant cycle of continuous tumor proliferation and distant metastasis is accelerated. Interestingly, mitochondrial dysfunction induces glycolysis and mediates senescence/failure of CD4⁺ or CD8⁺ T cells, and HCC progression [39]. The involvement of senescence in supporting malignancy through mediation of glycolysis has also been reported in TAMs [51] and CAFs [52]. These events provide the basis for the formation of an immunosuppressive TME and tumor persistence. Characteristics of senescence, such as epigenetic modifications, are additionally involved in the regulation of glycolysis. For instance, YTH N6-methyladenosine RNA binding protein F3 (YTHDF3) promotes aerobic glycolysis in HCC by enhancing phosphofructokinase liver type (PFKL) mRNA and protein expression in an m⁶A methylation-dependent manner [53]. In addition, Tregs activate a glucose competition-triggered nuclear kinase ATM protein-associated DDR in effector T cells in the TME, causing senescence and altered function that may contribute to tumor progression [54]. Interestingly, metabolic reprogramming-mediated SASP also appear critical for tumor proliferation and metastasis. In the progression of senescence in immune cells, impaired glucose metabolism causes dysregulation of NAD⁺ metabolism, leading to increased acquisition of SASP (including IL-1β, IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1)) and tumorigenic events [55]. Mechanistically, the high mobility group A/nicotinamide phosphoribosyltransferase/NAD (HMGA/NAMPT/NAD) signaling axis promotes the acquisition of pro-inflammatory SASP (IL-1β, IL-6, and IL-8) through enhanced glycolysis and mitochondrial respiration, ultimately exerting a tumor-promoting effect in ovarian cancer [56]. Notably, EVs are emerging pro-tumor mediators of the SASP, with reports of senescent tumors or normal cells contributing to the release of some SASP (IL-6/IL-12)-loaded EVs and acceleration of tumor progression [57]. For instance, EVs released from senescent fibroblasts contribute to tumor proliferation via the SASP pathway based on interactions with EPH receptor A2 (EPHA2) [58]. In addition, components of EVs derived from senescent fibroblasts can facilitate tumor growth by increasing the incidence of DNA damage and chromosomal instability [59].

Evidence from ongoing research may provide a new paradigm for immune checkpoint therapy of tumors. For example, the restriction of glycolysis in melanoma induces delayed T cell senescence and enhances the therapeutic benefits of immune checkpoint therapy [60]. Accordingly, we hypothesized that age-dependent epigenetic modifications alter immune phenotype and function by causing dysregulation of the glycolytic metabolism and accumulation of metabolite-related products, thereby remodeling an immunosuppressive TME and accelerating tumor proliferation and metastasis. Moreover, tumor immunosuppression induced by crosstalk between other senescence hallmarks, such as SASP, EVs, and DNA damage, and the immune microenvironment is of significant research interest.

2.3 Cellular senescence and lipid metabolism

Multiple enzymes are required for catabolism, digestion and absorption of fat to maintain the balance of the intracellular environment [61]. The high nutritional demands of tumor cells drives them to produce material and energy sources for self-proliferation and metastasis through regulating and utilizing lipid metabolism (fatty acid oxidation) [62]. A typical example is CUB domain-containing protein 1 (CDCP1), which stimulates fatty acid oxidation to supply energy for metastasis of triple-negative breast cancer [63]. Senescence and lipid metabolism are closely associated in multiple aspects of tumor progression. Existing findings suggest that lipid metabolism influences the immune microenvironment by regulating cellular senescence, thereby promoting tumor progression [64]. For example, immunoglobulin-like transcript 4/paired immunoglobulin-like receptor B (ILT4/PIR-B) increases fatty acid synthesis and lipid accumulation in tumor cells by activating MAPK extracellular signal-regulated kinase 1/2 (ERK1/2) signaling and supports lung cancer progression by inducing effector T cell senescence [64]. In addition, specific characteristics of senescence in liver cells may play a role in regulating lipid metabolism to influence tumor progression. Persistence of DDR promotes genomic instability and is involved in the induction of hepatitis B virus-associated HCC events through androgen and lipid metabolism [65]. On the other hand, deficiency of histone methyltransferase SET domain-2 inhibits H3K36me3 enrichment and cholesterol efflux gene expression, resulting in lipid accumulation and abnormal metabolism in HCC [66]. The significance of of lipid metabolism in shaping the immunosuppressive phenotype via regulating immune cells has been established. Lipid accumulation and enhanced metabolism, in turn, stimulate the differentiation and activation of TAMs [67] and confer resistance to anti-angiogenic drugs [68]. Previous studies have shown varying degrees of contribution of multiple cytokines to the development of metabolic dysfunction. In a mouse model of lipid metabolism, accumulation of p53 induced HCC-related SASP inflammatory responses (including upregulation of hepatocyte growth factor (HGF), TNF, IL-1β, and CCL2) and generated an immunosuppressive microenvironment supporting HCC development [69].

The high metabolic demand of tumors during proliferation is yet to be comprehensively investigated. In cases where the glycolytic metabolism cannot meet the needs of tumors, metabolic reprogramming switches glucose to lipid metabolism to provide the energy required for tumor development. For instance, increased fatty acid uptake promotes ovarian cancer cell survival under cisplatin-induced oxidative stress through enhanced β-oxidation [70]. A feasible hypothesis is that that DNA damage and epigenetic alterations in senescent cells affect the immune cell phenotype through their involvement in the regulation of lipid metabolism, thereby resulting in the formation of an immunosuppressive TME and tumorigenesis. Mechanistically, age-dependent DNA methylation impairs the function of elongation of very long chain fatty acids-like 2 (ELOVL2; a gene highly associated with epigenetic alterations, age prediction, and regulation of lipid metabolism) and disrupts lipid synthesis by inducing an increase in endoplasmic reticulum stress and mitochondrial dysfunction. These effects ultimately contribute to dysfunction of lipid metabolism and accelerated liver senescence [71]. In addition, during this metabolic reprogramming, the immune phenotype and function of B cells, T cells, and macrophages are altered, resulting in remodeling of the immunosuppressive TME and promoting an inflammatory microenvironment that favors the development of malignant disease [72].

2.4 Cellular senescence and amino acid metabolism

Among the several variables closely associated with tumor progression, amino acid degradation is another key aspect of tumor energy metabolism. Activation of glutamine metabolism coordinates non-essential amino acid fluxes within the tumor ecosystem. Mechanistically, RNA binding motif protein 4 (RBM4) modulates the activity of liver kinase B1 (LKB1; a regulator of amino acid metabolism) to favor glutamine-dependent survival of esophageal squamous cell carcinoma cells and counteract tumor cell senescence [73]. Dysregulation of amino acid homeostasis is reported to trigger senescence of epidermal keratinocytes and initiate SASP-dependent skin cancer migration via the glycine transporter protein solute carrier family 6 member 9/glycine transporter 1 (SLC6A9/GLYT1) [74]. Amino acid metabolism is a complex process incorporating multiple pathways that play a role in its contribution to tumor proliferation. The regulation of senescence-related diseases, such as formation of the pre-tumor ecotone, may be influenced by amino acid metabolism. Gasdermin D (GSDMD) and CASP11 are involved in acquisition of SASP (IL-1β and IL-1β-dependent IL-33). IL-33 release, in turn, stimulates Tregs, which contribute to HCC progression [75]. These findings support the concept that amino acid metabolism is involved in remodeling of the immunosuppressive microenvironment through the regulation of Treg cell senescence. The formation of this pre-tumor ecological niche is additionally linked with CAF metabolism and macrophage polarization [76, 77]. Indeed, along with the high energy demand for tumor proliferation, mitochondria may regulate the intrinsic crosstalk of multiple mechanisms (e.g., glycolysis, lipid metabolism, and amino acid metabolism) through metabolic reprogramming to collectively provide energy and raw materials for tumor growth [78]. However, limited information is available on this process at present. The association of different modes of metabolic reprogramming with tumor proliferation and invasion in the microenvironment warrants further investigation.

2.5 Cellular senescence-related metabolites shape the immunosuppressive TME

Accumulating evidence suggests that tumor metabolic reprogramming produces toxic metabolites that reshape the immune microenvironment to promote tumor survival and proliferation. Lactate accumulation and TME acidification exert significant effects on immune cell-mediated anti-tumor responses. Benefiting from the dynamic evolution of the TME, SASP is clearly involved in the shaping of the immunosuppressive TME through the release of multiple inflammatory factors. Interestingly, metabolites support this SASP-mediated release of inflammatory factors to some extent (for instance, glycolysis-derived lactate accelerates HCC growth by promoting the secretion of IL-23 and IL-17 [79]) and exacerbate the suppressive microenvironment (e.g., lactate prevents upregulation of nuclear factors in activated T cells and NK cells, leading to reduced interferon-gamma (IFN-γ) production and weakened melanoma immune surveillance [80]). Cellular senescence stress in CAFs drives glycolysis to produce lactic acid and promote breast cancer growth [52], while lactate released from tumor metabolism helps pre-cancerous cells escape senescence [81]. Tumor progression further promotes an acidic environment and release of associated senescence inflammatory factors as well as persistent tumor immunosuppression. Accordingly, we hypothesized that metabolites and cellular senescence-induced SASP promote each other to create an acidic microenvironment and jointly perpetuate the vicious cycle of tumor development. Interestingly, lactate has been shown to modulate the immunosuppressive phenotype of MDSCs, thereby contributing to radioresistance in pancreatic cancer [82]. Moreover, lactate-induced M2 polarization of TAMs promotes pituitary adenoma invasion through secretion of CCL17 [83]. These findings highlight the failure of tumor immunotherapy to account for the effects of metabolites on the tumor immune microenvironment.

Increased glutamine utilization affects the survival and death of selective types of immune cells and mediates a range of metabolic reprogramming modes to facilitate immunological escape in melanoma and colon cancer (e.g., through suppression of effector T cell survival) [84]. Notably, glutamine-dependent metabolic reprogramming alters the phenotype/function of immune cells by modulating cellular senescence to generate an immunosuppressive TME and drive tumor immune evasion. Tumor growth is associated with ongoing dysregulation of metabolic reprogramming and accelerated accumulation of deleterious metabolites, promoting the cycle of malignancy. The extracellular matrix machinery in CAFs activates glycolysis and glutamine metabolism through metabolic reprogramming to support invasion of head-and-neck cancer cells. This process orchestrates non-essential amino acid fluxes in the TME, leading to disruption of the ecological homeostasis of senescent cells [85]. Similarly, EV-carried circTRPS1 promotes the aggressive phenotype of bladder cancer by regulating the senescence process of CD8⁺ T cells through the circTRPS8/miR1-141p/GLS3 axis [86]. In addition, mitochondrial glutamine metabolism alters the microenvironment to favor tumor proliferation and treatment resistance in pancreatic and breast cancers [87, 88]. Other specific features of senescence are equally important for tumor growth. Tumorigenesis may be induced by accumulation of DNA damage and epigenetic alterations in cellular senescence, while remodeling by senescent cells could promote the secretion of associated inflammatory mediators to create an environment suitable for tumor survival. Moreover, sustained tumor growth induces a shift in energy metabolism from gluconeogenesis to amino acid metabolism to support tumor immune escape, followed by a vicious cycle of tumor proliferation. In view of the considerable heterogeneity of tumors, detailed analysis of the role of glutamine in each tumor type is essential for understanding the crosstalk in amino acid metabolism and developing novel strategies for targeted tumor therapy.

However, significant variations exist in the diverse tumor metabolic reprogramming products and their modulation of the immune microenvironment, making an exhaustive analysis impossible. The potential involvement of other tumor metabolites is equally interesting. For example, the fibroblast senescence-associated tumor metabolite, methylmalonic acid, promotes CAF activation to advance the progression of lung cancer metastasis [44]. Overall, metabolic reprogramming involved in cellular senescence directly alters the phenotype of immune cells and mediates remodeling of the immunosuppressive TME through the release of metabolites. In turn, proliferating tumors exacerbate metabolic reprogramming and cellular senescence to sustain this neoplastic cycle until systemic nutrient depletion.

3.1 Cellular senescence and anti‑tumor immune cells in the TME

3.2 Cellular senescence and immunosuppressive cells in the TME

6.1 Cellular senescence and cancer stem cells (CSCs)

CSCs are a primary cause of tumor resistance and disease recurrence. Hypoxia and metabolic reprogramming are critical components of the TME that are essential for rapid tumor growth and maintenance of CSC function [204]. Notably, cellular senescence and CSC function are commonly regulated by overlapping signaling pathways, including p16, p21, and p53, suggesting that cellular senescence drives genetic reprogramming and stem activation to contribute to CSC-mediated metastasis and treatment resistance [205]. In addition, increased cancer stemness may be associated with the CAF-mediated promotion of MDSC function and chemoresistance [155]. However, accumulation of senescent cells over time may mediate the expression and secretion of SASP-associated pro-inflammatory chemokines and cytokines, such as IL-6, IL-8, and IL-1α, which have been shown to support the pro-tumorigenic phenotype of CSCs via paracrine signaling in prostate cancer [201, 206]. The hypoxic TME is hypothesized to activate CSCs from a dormant state, thereby increasing their survival following exposure to stress conditions. Earlier studies have confirmed that hypoxia-mediated HIF1-α and HIF2-α contribute to the survival and activation of CSCs in the TME and underlie glioma resistance and EMT [207, 208]. This pro-tumor effect may be attributed to release of a SASP-like secretome from the hypoxic microenvironmentincluding inflammatory factors, such as IL-8, IL-1β, IL-2, IL-212, CXCL213, and CXCL212 [209]. Interestingly, a link between hypoxia and senescence in CSCs has been confirmed. In this study, hypoxia affected senescence and maintained the pro-oncogenic stem cell phenotype by regulating HIF-1α-mediated expression of p21 in CSCs and other progenitor cells [210]. Additionally, tumor cell-mediated metabolic reprogramming is reported to contribute to the maintenance of cancer stemness. For example, in breast cancer cells, dysregulation of mitochondrial metabolism induces glycolysis to support the proliferation of CSCs [211]. HIF-1 activation drives autophagy, glycolysis, and fibroblast senescence in CAFs, ultimately sustaining cancer stemness through metabolic reprogramming to promote breast cancer growth [212]. This finding suggests that intrinsic crosstalk between hypoxia and metabolic reprogramming in the senescent TME creates an inflammatory milieu conducive to activation and stemness maintenance of CSCs.

6.2 Cellular senescence and angiogenesis

Angiogenesis, a process that provides the nutrients and oxygen required for tumor growth, is crucial factor in tumor invasion and metastasis [213]. Numerous studies have investigated the effects of angiogenesis in the TME on tumor invasion and metastasis. Ischemic retinal cellular senescence-mediated SASP is reported to promote pathological angiogenesis by reshaping the inflammatory environment through secretion of IL-6, IL-8, and vascular endothelial growth factor (VEGF) [188]. Moreover, CXCL1 secreted by colorectal cancer cells promotes tumor angiogenesis by inducing a senescent phenotype in stromal fibroblasts [214]. Recent studies have focused on inducing pathological vascular normalization of tumors and limiting their malignant progression triggered by increased hypoxia and senescence [215]. Hypoxia-dependent regulation of the m⁶A reader, YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) (associated with senescence characteristics), is implicated in enhanced inflammation and angiogenesis critical for HCC invasion [216]. Furthermore, hypoxia-induced SASP releases the pro-inflammatory factor, TNF-α, which activates NF-κB, leading to VEGF production. This sequence of events promotes angiogenesis and metastasis [217]. Interestingly, angiogenesis is facilitated by metabolic reprogramming in hypoxic TME. HIF-1α regulates P53 expression in hypoxic tumor cells, which influences cellular senescence and promotes tumor proliferation through enhanced glycolysis and angiogenesis [218]. High BCAT1 expression supports angiogenesis and malignant progression of gliomas by regulating hypoxia, glycolysis, and cellular senescence to induce an immunosuppressive state [219]. In malignant TME, both senescent and non-senescent vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) appear to accelerate tumor growth by supporting angiogenesis to an extent. The involvement of vascular endothelial cells (VECs) and VSMCs in angiogenesis in a senescent TME has been further explored. Th17/IL-17 induces VEC senescence via activation of the NF-κB/p53/retinoblastoma (NF-κB/p53/Rb) signaling pathway [220]. Notably, exendin-4 alleviates angiotensin II-induced senescence in VSMCs by inhibiting Rac1 activation through a cyclic adenosine monophosphate/protein kinase A-dependent (cAMP/PKA-dependent) pathway [221]. Subsequently, inflammatory factors released by senescent VECs and VSMCs may stimulate immunosuppression and angiogenesis [222, 223]. However, in a malignant TME, reduced senescence accompanied by VECs and VSMCs has also been shown to promote angiogenesis and metastasis. Vascular endothelial growth factor (VEGF) is considered the most potent and abundant vascular growth factor in angiogenesis, with an established role in promoting tumor progression. Cellular senescence (with the exception of VECs and VSMCs) is reported to induce the release of SASP (VEGF, IL-6, IL-8, CXCL1, and TNF-α) to reshape the inflammatory environment, thus supporting pathological angiogenesis and bladder cancer growth. This process is accompanied by an adaptive response to hypoxia and metabolic reprogramming [224]. Targeting pro-angiogenic cellular senescence may provide an innovative avenue for treatment of solid tumors, given the therapeutic benefits of anti-angiogenic therapy. Moreover, the specific mechanisms by which senescence affects other pathways of VEGF and TME angiogenesis (e.g., hypoxia and metabolic reprogramming) require further investigation.

6.3 Cellular senescence and tumor metastasis

Senescence-mediated enhancement of tumor invasion and metastasis has been demonstrated in cervical cancer [225], breast cancer [226], melanoma [227], and prostate cancer [228]. Tumor metastasis is a multi-step process designated the “invasion-metastasis cascade” [213, 229]. Therefore, the precise involvement of senescence at each stage of this process, from primary tumor cell development to the formation of metastatic ecological niches, should be explored. For example, senescence-related reprogramming promotes cancer stemness in lymphoma and is a key factor in metastasis [205]. Cellular senescence-mediated acquisition of SASP induces tumor EMT and distant metastasis [230]. Moreover, vascular permeability factor/VEGF (VPF/VEGF) delays and induces escape from senescence in human dermal micro-VECs [231], which lends credence to the possibility of transendothelial migration of tumor cells. Given the effects of hypoxia and metabolic reprogramming on immunosuppression and chronic inflammation, it is hypothesized that these factors, in conjunction with cellular senescence, promote tumor proliferation and metastasis. For example, overexpression of TNF receptor-associated factor 6 (TRAF6) and H2A histone family member X (H2AX) and γH2AX-mediated HIF-1α enrichment in the senescent environment lead to HIF-1α-driven glycolysis and an inflammatory response, promoting metastasis of lung cancer [232, 233]. Virtually all established mechanisms of tumor metastasis involving CSCs [234], angiogenesis [218], EMT [235], chemoresistance [236], and autophagy [237] are related to hypoxia and metabolism to varying degrees. However, the potential roles of cellular senescence and metabolic reprogramming in other metastatic processes, such as signaling networks for the entry and exit of tumor cells from dormancy as well as tumor-associated metastatic colonization and evolution, are yet to be determined.

6.4 Cellular senescence and therapeutic resistance

Tumors frequently develop resistance to multiple treatment modalities, ranging from conventional radiotherapy and chemotherapy to modern targeted treatments and immunotherapy, resulting in distant metastasis. In-depth understanding of senescence-mediated mechanisms of resistance is necessary to improve therapeutic efficacy. D-galactose is reported to induce cell senescence in astrocytes, leading to chemoresistance and astrocytoma metastasis [238]. RagC GTPase activates mTOR signaling and tumor chemoresistance by promoting senescence in HCC [239]. Interestingly, the mechanisms underlying TME tandem-induced therapeutic resistance are multifaceted. For instance, hypoxia-mediated HIF-1α regulates cellular senescence in the TME to achieve colorectal cancer chemoresistance [240]. Notably, hypoxia induced by tumor proliferation can trigger mitochondrial dysfunction to regulate glucose uptake and utilization, in addition to promoting angiogenesis and chemoresistance in renal cell carcinoma [241]. This mitochondrial dysfunction may be attributed to an immunosuppressive inflammatory environment produced by hypoxia and metabolic reprogramming triggered by the activation of senescence signaling during tumor proliferation and in the TME. The cascade includes multiple cell biological processes (such as angiogenesis, EMT, and CSCs) that co-support tumor chemoresistance [242]. Autophagy-associated ATG5 controls mitotic slippage, thus inducing cell senescence-dependent SASP and promoting pancreatic cancer chemoresistance, migration, invasion, and angiogenesis via paracrine secretion [243]. Angiogenesis in the senescent TME may drive endocrine secretion in breast cancer cells to achieve resistance to tamoxifen [244]. Furthermore, activation of the NF-κB/HOX transcript antisense RNA (NF-κB/HOTAIR) axis links cellular senescence, DDR, and chemoresistance in ovarian cancer [245]. Interestingly, this chemoresistance continues to be enhanced through several ways to achieve sustained tumor malignancy. Senescent CAFs affect metabolic programs in MDSCs through regulation of IL-6- and IL-33-mediated chronic inflammation and promote cancer stemness in the TME to confer resistance to chemotherapy [155]. Moreover, chemotherapy-induced cellular senescence facilitates CSC growth to enhance tumor chemoresistance [246].

Radioresistance presents another considerable therapeutic challenge. Ionizing radiation effectively induces senescence in glioma cells. Senescent stromal cells can support the proliferation of neighboring glioma cells by secreting pro-inflammatory SASP factors, ultimately inducing radioresistance and disease recurrence [247]. Telomere dysfunction, a feature of cellular senescence, is additionally reported to promote radioresistance of oral cancer cells [248]. Current research on cellular senescence and tumor radioresistance has focused on the inflammatory environment shaped by the acquisition of SASP [249]. Further investigation of the crosstalk between specific features of senescence (DNA damage or epigenetics) and tumor biological behavior (autophagy, EMT, angiogenesis) would be of significant interest [250, 251].

Notably, immunotherapy enhances the anti-tumor activity of chemotherapy via suppression of NK cell-induced senescent cells [252]. Therefore, elucidation of the mechanisms underlying cellular senescence-mediated chemoresistance/radioresistance may yield promising insights for application in tumor immunotherapy. Future research should focus on the effects of signaling exchanges of metabolic programming, hypoxia, and other TME components on cellular senescence features, such as DNA damage and epigenetics.

6.5 Tumor therapy-induced cellular senescence

Cancer cells can enter a state of senescence upon exposure to chemotherapy, radiation, or targeted treatments, a process termed “therapy-induced senescence” (TIS). This state entails arrest of the cell cycle, which is primarily mediated through activation of p53/p21WAF1 and/or p16INK4A/Rb pathways [253]. In tumors such as malignant pleural mesothelioma, an increase in markers of senescence, such as PAI1 and p21WAF1, has been reported following neo-adjuvant chemotherapy (NAC) [254]. While the primary goal of cancer therapy is to reduce tumor growth by triggering cell death, the treatment can also damage the TME, including stromal cells, leading to significant accumulation of senescent cells that can affect various components of the TME and potentially alter the overall response to the tumor. Secreted factors of senescent cells, known as the senescence-associated secretory phenotype (SASP), are capable of promoting growth, new blood vessel formation, migration, and invasion of surrounding cells, impacting the overall behavior of cancer and stromal cells in the TME [255].

Furthermore, the effects of SASP vary depending on the targeted cell and its surrounding environment, adding to the complexity of the function of senescent cells within the TME. Accumulating SASP factors, including IL-6, IL-8, and TNF-α, can promote the senescent state through self-stimulating and neighboring stimulating mechanisms, inhibiting key processes of tumor growth and metastasis [256]. Conversely, SASP components, such as VEGF, EGF, and FGF, may erroneously promote differentiation and the formation of new blood vessels in adjacent tissues. Furthermore, several SASP factors and pathways, including TGF-β1, NF-kB, CXCL1, IL-8, and cGAS-STING signaling, are capable of fostering senescence in surrounding cells via paracrine effects [257]. Therefore, the efficiency of TIS in the context of damaged TME is influenced by various elements, including the volume of secreted molecules, the signaling pathways activated, and the temporal dynamics of SASP evolution. Such factors reflect the complexity and variability of the senescence response and its changes depending on particular parameters and pathophysiological settings [258, 259]. TIS can induce cellular senescence via SASP in a manner that indirectly influences tumor growth by promoting activities, such as tumor cell proliferation, formation of new blood vessels, transition to a more invasive cell type, epithelial-mesenchymal transition (EMT), and ability of the tumor to evade the immune system.

6.6 Cellular senescence and autophagy

In the malignant TME created by tumor progression, autophagy acts as a dynamic degradation and recycling system that regulates tumor survival and metastasis while influencing tumor aggressiveness [260]. Activation and inhibition of autophagy represents an adaptive change in tumor response to hypoxia and metabolism. Compelling evidence supports the theory that autophagy-related mechanisms of tumor progression are linked to factors such as metabolic and senescence [261].

Theoretically, autophagy should exert an anti-tumor effect based on its powerful stabilizing function and timely removal of “dangerous molecules” from the body. Nevertheless, autophagy has both beneficial and detrimental effects on tumors. Given the pro-tumorigenic nature of autophagy, autophagy of non-tumor cells provides nutrients to tumor cells and suppresses CD8⁺ T cell-mediated anti-tumor immunity, thereby promoting the survival and metastasis of cancer cells [262, 263]. Indeed, it is currently thought that this difference is a conflict between the anti-tumor and pro-tumor effects of autophagy, which may depend on the stage and environment in which autophagy occurs. For example, before tumorigenesis, activation of autophagy inhibits tumorigenesis; in advanced tumor stages, activation of autophagy may in turn promote tumor growth and metastasis [264]. Artemisinin inhibits cell growth in colorectal cancer by promoting ROS-dependent cellular senescence and autophagy [265]. Autophagy-associated ATG5 in breast cancer supports tumor chemoresistance by inducing SASP-associated paracrine tumorigenicity [243]. This may be attributed to differences in the type of cellular processes and inflammatory factor release mediated by autophagy/senescence at different stages of the tumor. In the TME, autophagy can be induced by stress signals both inside and outside the advanced tumor cell, including metabolic stress, hypoxia, senescence stress and immune signals. HIF-1α overexpressing in MSCs derived EVs ameliorate hypoxia-induced pancreatic β-cell apoptosis and pancreatic β cell senescence by activating YTHDF1-mediated autophagy [266]. Cannabinoid type 2 receptor (CB2R) activation regulates transcription factor EB-mediated (TFEB-mediated) autophagy and accelerates mitochondrial damage and inflammatory factor release through lipid metabolism [267]. However, in the face of hypoxic, metabolic, and cellular senescence stress, autophagy may work synergistically in multiple ways to maintain tumor proliferation. In the hypoxic TME, CSCs senescence leads to the release of inflammatory products through metabolic reprogramming to shape the immunosuppressive TME and chronic inflammatory environment conducive to testicular cancer proliferation and metastasis [268]. Subsequently, activation and homeostatic maintenance of autophagy drive the tumorigenicity and cellular differentiation of CSCs, while autophagy-mediated activation of CSCs drives tumor angiogenesis [269], EMT [270], therapeutic resistance [271] in diverse levels. Notably, autophagy also further accelerates tumor invasion and metastasis by promoting an intrinsic angiogenesis-EMT/EMT-chemoresistance/angiogenesis-chemoresistance association through the lung cancer metastasis cascade and feedback loops [272-274]. These findings highlight the critical interaction between autophagy and senescence and further confirm the biological significance of cellular senescence in TME hypoxia and metabolic programming.

6.7 Cellular senescence and rhythms

Circadian rhythms exert a significant impact on physiological and metabolic functions (including sleep, immune, endocrine and vascular biology) and their disruption is associated with increased risk of tumor metastasis [275]. Disturbances in biological rhythms lead to increased ROS production and melatonin secretion, which affect sleep, ultimately causing cellular senescence. These findings indicate that hormone secretion and metabolic regulation serve as a bridge between circadian rhythms and cellular senescence [276]. Considering the strong association of senescence with age-related metabolic diseases, senescence-regulated early growth response 1 (EGR-1) induces rhythm disruption and accelerates age-related metabolic dysfunction in the liver [277]. Disruption of circadian rhythms causes an imbalance in immune cells, which may affect the tumor immune response and consequently influence cancer progression. Loss of rhythmic KLF transcription factor 4 (KLF4) expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, which may underlie the loss of protective immune responses in age-related diseases, including tumors [278]. Conversely, maintenance of circadian rhythm homeostasis in DCs and CD8⁺ T cells is reported to enhance the anti-tumor immune response and suppress melanoma growth [279]. However, due to interactions of tumor cells with stromal cells in the TME, expression of the circadian regulatory gene Bmal1 is dysregulated, inducing fibrinolytic enzymes to promote conversion between CAFs and myofibrillar fibroblasts via activation of TGF-β, thereby promoting proliferation and metastasis of colorectal cancer [280]. Disruption of circadian rhythms in the microenvironment is significantly associated with angiogenesis and chemoresistance [281, 282]. In addition, autophagy regulates biological rhythms by degrading the core clock protein CRY1, which controls glucose metabolism [283]. Therefore, circadian dysregulation-mediated metabolic reprogramming of senescence initiates tumorigenesis and supports metastasis through a cascade of biological behaviors.

However, limited information is available on the unique expression and functional patterns of the cell-autonomous biological clock in different tumor types. Furthermore, little is known regarding the potentially common core clock signals existing between cancer and pluripotent stem cells that may diverge at some stage of cellular differentiation. These insights are critical for the development of effective therapeutic strategies, which may involve restoring functional clocks and reversing tumor epigenome plasticity.

6.8 Extracellular matrix

The extracellular matrix (ECM), a crucial component of the TME, is composed of a number of proteins, including collagen, fibronectin, hyaluronic acid, laminin, and proteoglycans [284]. Earlier research has conclusively shown that ECM integrity markedly declines with age. Reduced collagen density and variations in size and thickness of ECM fibers that weaken structural integrity are two physical ageing-associated alterations in ECM [285]. Compared to their more mature, senescent counterparts, young dermal fibroblasts exhibit a higher output of ECM constituents, including proteoglycans, glycoproteins, and proteins that maintain cartilage integrity [286]. Young fibroblasts are responsible for producing key elements of the extracellular matrix (ECM), in particular, hyaluronic acid and proteoglycan-linked protein 1 (HAPLN1) [287], which plays a vital role as a crosslinker to stabilize aggregates of proteoglycan monomers. Notably, the production of HAPLN1 decreases in aged fibroblasts, highlighting the intricate relationship between tumor cells and fibroblasts. Earlier studies have additionally demonstrated the significance of LOXL1 in facilitating cancer cell migration via the ECM, with impaired secretion reported in aging fibroblasts [288]. The changes in ECM components secreted by aging fibroblasts lead to a reduction in collagen density and degree of fiber crosslinking, alongside significant enhancement of fiber alignment. These modifications collectively facilitate the invasion of melanoma cells.

Accumulation of senescent matrix components linked to the SASP with age can promote the release of soluble factors that drive remodeling of the ECM and contribute to matrix sclerosis within the local environment. This process is critical in linking the ECM to the TME, as it enhances ECM crosslinking and sclerosis, facilitating tumor dissemination and advancement [289]. While senescence alters the ECM structure, the local build-up of senescent stromal cells associated with SASP may create tumor-specific habitats necessary for disease progression. For instance, lung malignancies are directly correlated with age and increased ECM rigidity, crosslinking, and collagen density [290], highlighting the importance of ascertaining the role of SASP cell accumulation in tumorigenesis within these soft tissue settings during senescence. Similarly, changes in ECM density due to senescence are linked with the development of breast cancer, whereby reduced integrity of the basement membrane or myoepithelial layer can enhance tumor cell interactions with ECM components, potentially establishing a pre-metastatic niche [291].

Remodeling of the ECM during tumor development has a significant impact on immune cell function. Components of the ECM, such as collagen and fibronectin, activate the PI3K/AKT pathway, which aids in the immune evasion of cancer stem cells (CSCs) [292]. Furthermore, ECM proteins, such as monomeric collagen type I, attract immunosuppressive cells, including T regulatory cells (Tregs) and Tumor-Associated Macrophages (TAMs), which support CSC survival by inhibiting the recruitment of anti-tumor immune cells [8]. Conversely, stabilizing collagen to reduce ECM density and tumor stiffness can facilitate T cell migration and improve the efficacy of anti-PD-1 therapy [293]. These findings highlight the critical role of physical alterations in the ECM in regulating immune and tumor cell migration. Ageing directly influences the specificity and functionality of immune cells in both the systemic and localized environments. Elucidation of the effects of ECM structure and functionality on tumor growth should provide opportunities to identify novel therapeutic targets that can inhibit both tumor proliferation and metastasis.

AUTHOR CONTRIBUTIONS

Fusheng Zhang drafted this review and designed the figures; Junchen Guo and Shengmiao Yu completed the data collection and provided editorial assistance; Youwei Zheng, Meiqi Duan, Liang Zhao and Yihan Wang gave some valuable suggestions; Xiaofeng Jiang and Zhi Yang provided the design and revision of the manuscript; Xiaofeng Jiang and Zhi Yang obtain funding supports. All authors made substantial, direct and intellectual contribution to the review. All authors read and approved the final manuscript.