Immunosenescence and Cancer: Cellular Aging Programs That Reshape Antitumor Immunity

Abstract

Immunosenescence refers to the age-associated decline in immune competence, driven, in part, by the senescence-associated secretory phenotype (SASP), which maintains chronic low-grade inflammation (“inflammaging”). Aging alters both innate and adaptive immunity, marked by impaired phagocytosis, antigen presentation, and cytotoxicity in macrophages, dendritic cells, neutrophils, and NK cells, as well as dysfunctional B-cell subsets, thymic involution, reduced TCR diversity, and accumulation of senescent CD4⁺CD28⁻ and CD8⁺CD57⁺KLRG1⁺ T cells. Within tumors, these alterations promote immune evasion through SASP-derived IL-6 and TGF-β, expand myeloid-derived suppressor cells, and favor angiogenic and immunosuppressive macrophage states. Cytotoxic lymphocyte and NK-cell dysfunction further weakens antitumor immunity and limits the responses to checkpoint inhibitors and chimeric Ag receptor T-cell therapy in older patients. In this review, we summarize the cellular and molecular mechanisms underlying immune cell aging and outline how immunosenescence programs reshape the tumor microenvironment and influence cancer immunotherapy outcomes.

INTRODUCTION

Aging is accompanied by a gradual decline in immune function, a phenomenon known as immunosenescence. This process involves alterations in both innate and adaptive immunity, including impairment of pathogen recognition, reduction in lymphocyte diversity, and dysregulation of inflammatory responses. Immunosenescence, an age-associated process of biological decline, is distinct from immune exhaustion, which develops in response to chronic Ag exposure and persistent inflammatory stimulation (1). However, the two concepts can be confused due to their shared feature of impaired effector function. Despite this overlap, these processes are driven by fundamentally different molecular mechanisms. Immune exhaustion is characterized by a state of reversible functional suppression, often marked by increased expression of inhibitory receptors such as PD-1 (2), whereas immunosenescence refers to the loss of proliferative capacity due to cell-cycle arrest, accompanied by broader phenotypic and functional alterations that collectively lead to immune dysfunction (3,4).

At the cellular level, immunosenescence manifests as impaired maintenance of naïve and memory T cells, contraction of TCR diversity, and accumulation of functionally exhausted T cells (5,6). B cells also exhibit age-associated defects, including diminished class-switch recombination and reduced Ab affinity (7). Innate immune cells, such as macrophages, dendritic cells (DCs), and NK cells, display dysregulated activation, reduced phagocytic capacity, and altered cytokine production, collectively weakening the defense and immune regulation in hosts (8,9,10).

Inflammaging, a state of chronic low-grade inflammation that develops with advancing age, is a fundamental hallmark of age-related immunosenescence (11). Inflammaging is recognized as a crucial driver of age-related diseases and an important mediator of tissue damage, increased susceptibility to diseases, and disruption of immune homeostasis (12).

Given the rapidly growing global older adult population, understanding the mechanisms underlying immunosenescence has become a matter of clinical and societal urgency. Importantly, among age-associated diseases, cancer is uniquely dependent on effective immune surveillance, and immune aging critically shapes tumor initiation, progression, and the response to therapy (13). This review focuses specifically on how immunosenescence reprograms antitumor immunity, remodels the tumor microenvironment (TME), and modulates the efficacy of cancer immunotherapies such as checkpoint blockade and chimeric Ag receptor (CAR) T-cells.

CHARACTERISTICS OF CELLULAR SENESCENCE

Molecular and functional hallmarks of senescent cells

Cellular senescence is a broadly defined aging-associated cellular state observed across multiple cell types. One of the early features commonly associated with senescent cells is alterations in chromosomal structure and function. Telomere shortening is a widely recognized indicator of aging (14,15). Telomeres are repetitive DNA sequences at the ends of chromosomes that progressively shorten with each cell division. Critically short telomeres impair cellular function and, ultimately, induce cell death (16). In addition, increased expression of cell cycle regulators, such as p16, p21, and p53, is commonly observed in senescent cells. These proteins halt proliferation in response to accumulated DNA damage or stress, ultimately driving cells into a senescent state (17,18). Senescent cells, which accumulate with age across multiple tissues, adopt a characteristic senescence-associated secretory phenotype (SASP), characterized by the release of pro-inflammatory cytokines and factors, including IL-1, IL-6, IL-8, TNF, VEGF, and matrix metalloproteinases (19). Epigenetic alterations are important markers of cellular senescence (20). Age-related changes in DNA methylation patterns can serve as predictors of biological age (21). Furthermore, increased activity of senescence-associated β-galactosidase (SA-β-gal) is frequently observed in aged cells and remains one of the most widely used experimental markers of cellular senescence (11). Collectively, these molecular and functional markers provide complementary insights into immune cell aging, and their integrated analysis enables more precise assessment of the degree of cellular senescence (Fig. 1).

Figure 1. Characteristics of cellular senescence. Aging causes increased levels of intracellular ROS, SA-β-gal activity, telomere shortening, and altered DNA methylation. These changes, along with the increased expression of cell cycle inhibitors, such as p16, p21, and p53, lead to decreased cellular function, increased apoptosis, and decreased proliferation. Senescent cells exhibit the SASP, which induces chronic inflammation in the tissue microenvironment and further impairs the function of surrounding cells.

Immunosenescence shares many molecular and functional features with cellular senescence. For example, excessive oxidative stress contributes to immune cell aging by inducing T-cell apoptosis and promoting telomere and mitochondrial dysfunction (22). SASP factors hinder the clearance of senescent and pathogenic cells by weakening both innate and adaptive immune responses while simultaneously driving phenotypic dysfunction in immune cells (11). However, the manifestation of these features varies depending on immune cell type and biological context. In immune cells, canonical features of senescence are often uncoupled and do not necessarily manifest in their entirety (23). Even without satisfying all conventional senescence criteria, each immune cell type develops distinct aging-associated features that contribute to the overall decline in immune function. In the following section, we discuss aging-associated features described in specific immune cell types.

INNATE IMMUNOSENESCENCE

Innate immunity involves the actions of macrophages, DCs, NK cells, and neutrophils, which play important roles in the initial defense against external infectious agents. Aging of hematopoietic stem cells (HSCs), which are responsible for generating a broad spectrum of innate immune cells, is associated with reduced TGF-β signaling, resulting in a skewed differentiation toward the myeloid lineage (4). This characteristic of aging is linked to the innate and adaptive immunity network, which contributes to the development of additional infectious diseases in older adults (Fig. 2).

Figure 2. Changes in immune cell function and systemic impact of immunosenescence. Aging is accompanied by a functional decline in both innate and adaptive immune cells by dysfunction in aged HSCs and the thymus. These changes include decreased NK cell activity, decreased Ag-presenting capacity of DCs, altered neutrophil phagocytosis and NETosis, and decreased IL-4/STAT6 signaling in macrophages. CD4⁺ and CD8⁺ T cells exhibit decreased proliferation and TCR rearrangement, along with increased inflammatory signaling. B cells exhibit decreased developmental stages (pro-B and pre-B) and plasma cell differentiation, along with impaired mitochondrial function. These changes disrupt immune homeostasis and promote chronic inflammation.

Macrophage dysfunction

Macrophages undergo changes in their functional homeostasis and tissue immune responses because of aging. In aged mice, the number and ratio of monocytes/macrophages increases in bone marrow cells (24) and aged macrophages have increased cell size, an elongated shape, and decreased F-actin content (8). The extent of phagocytosis and chemotaxis, which are considered important functions of macrophages, decreases with age (8). Macrophages normally have a circadian rhythm, and their phagocytic activity peaks at night. However, as the expression of KLF4, which functions in monocyte differentiation and in the establishment of M2 macrophage polarization states, decreases with aging, this circadian function is inhibited and the phagocytic rhythm is disturbed (25). Efferocytosis, the ability to clear apoptotic cells, is also defective in aged macrophages, resulting in an increase in the number of senescent neutrophils in the circulation and bone marrow (26). In aged macrophages, their migration and phagocytosis are markedly reduced by MYC and USF1 transcription programs (8). In aged bone marrow macrophages, the expression of inflammatory mediators, including Myc, Foxm1, Nfyb, Usf1, Cdkn1a, Cdkn2a, Tnfa, Il1b, Il18, and Ccl2 is markedly increased. This increase in the acquisition of inflammatory properties is because of the decrease in STAT6 expression, where the anti-inflammatory cytokines Il4ra, Il4, and Il13 were decreased in various tissues of aged mice. The IL-4–STAT6 axis alleviates the cellular senescence of macrophages by regulating DNA repair and the cell cycle (27). In aged tissues of mice and humans, pro-inflammatory M1-like macrophages exhibit high expression of the NAD-consuming enzymes CD38 and CD157, both of which function as NAD hydrolases (28). Furthermore, a decline in de novo NAD⁺ synthesis, mediated by increased oxygen consumption and alterations in the kynurenine pathway in aged macrophages, contributes to reduced NAD⁺ levels and exacerbates innate immune dysfunction in age-associated diseases (29). This enhanced pro-inflammatory profile propagates senescence to distant tissues, thereby driving systemic aging and age-related dysfunction through extracellular vesicle (EV)-mediated induction of paracrine senescence (24). miR-378a-3p in EVs induces inflammation and metabolic abnormalities through the inhibition of PPARα signaling (24). Senescent macrophages not only impede initial defenses against pathogens but also promote tissue inflammation, potentially leading to systemic immune dysfunction. As a target for age-related diseases, further research is needed to identify therapeutic approaches that can inhibit macrophage senescence or reverse its functional decline. Furthermore, tissue-resident macrophages, such as Kupffer cells and alveolar macrophages, perform specialized functions in each tissue and may exhibit different aging-related characteristics depending on the tissue environment. Therefore, research addressing functional changes in tissue-specific senescent macrophages present in older adults is also warranted.

DC aging and impaired antigen presentation

Aged DCs exhibit reduced AKT phosphorylation and PI3K pathway activation, resulting in impaired Ag uptake and reduced migratory capacity (30). Aged DCs downregulate the expression of B2m and Tap1, which are related to Ag presentation, and upregulate the expression of Apoe, which can suppress Ag presentation (31). In aged mice, conventional bone marrow-derived DCs exhibit reduced expression of cytokines such as IL-10 and IL-12p70, along with impaired migratory activity (32). Notably, adjuvant-driven hyperactivation of aged DCs promotes their excessive migration to lymph nodes and triggers inflammasome activation, leading to IL-1β secretion and thereby enhancing antitumor immunity in older adult hosts (32). Aging also alters the interactions of DCs with other immune cells. In aged lymph nodes, follicular DCs occupy a smaller area and exhibit reduced expression of CXCL13, a key chemotactic factor in B cells (33). Aged plasmacytoid DCs display defective phosphorylation of the transcription factor IRF7, resulting in impaired secretion of type I and type III IFNs. This deficiency diminishes the ability of CD4⁺ and CD8⁺ T cells to induce effective antiviral responses (34).

DCs play an important role in inducing NK-cell activation. In a study, splenic DCs from old mice showed decreased expression of IL-15, IL-18, and IFN-α, resulting in reduced frequencies of activated NK cells, as confirmed from the reduced expression of CD69 and granzyme (35). In virus-infected aged mice, impaired migration of DCs to the draining lymph node leads to reduced infiltration of inflammatory monocytes and diminished CXCL9 production, thereby limiting NK-cell recruitment (9). In the TME of aged cells, conventional type 1 DCs and NK cells strongly interact with each other through the Clec2d–Klrb1b axis to suppress NK-cell function, resulting in a decrease in the ratio of NK cells to DCs (31). This dysfunction leads to the restriction of T-cell priming and the promotion of tumor-infiltrating age-associated dysfunctional T-cell formation. Aged DCs not only exhibit reduced Ag-presenting capacity but also impair T cell and NK-cell function, leading to deficiencies in both initial defense and subsequent adaptive immunity. Therefore, DC aging emerges as a central driver of immune dysfunction across multiple cellular compartments. However, the functional heterogeneity of aged DC subsets in humans, their roles in age-related diseases, and their dynamic interactions within immune networks remain incompletely understood and warrant further investigation.

NK-cell aging and loss of cytotoxic competence

The proportion of CD56⁺ NK cells in the peripheral blood increases with aging, but their proliferative capacity declines (36). Activation through CD158d (KIR2DL4) induces a senescent phenotype in NK cells, characterized by p21-dependent cell cycle arrest, morphological enlargement, vascular remodeling, angiogenesis, and acquisition of an SASP (37). Aging also reshapes NK-cell subsets, with a decline in the number of CD56^bright cells and an increase in that of terminally differentiated CD56^dimCD57⁺ NK cells (38). These senescent-like NK cells display impaired cytokine production, reduced proliferative responses, and telomere shortening (38,39). Functionally, NK cytotoxicity diminishes with age due to decreased perforin and granzyme release, reduced conjugate formation with target cells, and impaired Ab-dependent cytotoxicity (39,40). Increased expression of inhibitory receptors, such as NKG2A, further dampens NK cytotoxicity in older adults (41). Although extensive research has characterized the dysfunctions of senescent NK cells, such as angiogenesis and reduced cytotoxicity, the underlying molecular mechanisms and altered signaling pathways remain poorly defined. Elucidating these pathways will be critical for developing targeted interventions to restore effective early immune surveillance in older adults.

Neutrophil aging and altered inflammatory dynamics

Neutrophil aging is driven by microbiota-derived signals transmitted through the TLR–MyD88 pathway (42). Depletion of the microbiota markedly reduces the number of circulating aged neutrophils. These aged neutrophils are phenotypically defined as CXCR4^highCD62L^low and are characterized by increased α_Mβ₂ integrin activity, along with elevated expression of CD11b, CD49d, ICAM1, and TLR4 (42,43). Obesity also influences neutrophil aging. A high-fat diet increases the infiltration of aged neutrophils into the liver and adipose tissue, thereby promoting inflammation and altering immune cell architecture during the development of obesity (44). Functionally, aged neutrophils exhibit altered autophagy; however, these findings remain somewhat controversial. Some studies have reported upregulation of autophagy-related pathways in aged neutrophils (45), suggesting a compensatory mechanism for survival under stress conditions. However, most evidence indicates a decline in autophagic capacity with aging, which contributes to impaired efferocytosis, persistent inflammation, and defective host defenses (46). In addition, aged neutrophils exhibit reduced ROS production and diminished neutrophil extracellular trap formation (47). Aged neutrophils exhibit structural and functional alterations, including a reduced number of microvilli and impaired rolling (48). Conversely, another study demonstrated that the activation of aged neutrophils enhanced phagocytic activity and increased their rolling and adhesion within blood vessels (49). While the phenotypic features that distinguish aged neutrophils are well established, the precise contributions to disease progression in older adults remain unclear. Accumulating evidence indicates that neutrophil aging is highly heterogeneous, with functional properties that vary according to tissue environment and disease state.

ADAPTIVE IMMUNOSENESCENCE

Adaptive immunity refers to an Ag-specific immune response that plays a crucial role in the pathogenesis of various chronic diseases, cancer, and vaccine efficacy. The bone marrow and thymus, which are involved in the production of T and B cells, contribute to a large component of adaptive immunity during the aging process (Fig. 2). In older adults, HSCs exhibit a myeloid-biased phenotype that results in reduced lymphocyte production (50). Age-related thymic degeneration results in reduced thymic weight and total cell number. The accumulation of age-associated thymic epithelial cells, characterized by diminished Ag-presenting ability and elevated expression of epithelial-to-mesenchymal transition (EMT)-related genes, further impairs T-cell development (3,51,52).

T-cell senescence and repertoire contraction

An analysis of peripheral blood mononuclear cells from older adults revealed an increased frequency of CD4⁺ T cells, accompanied by a concomitant reduction in the number of CD8⁺ T cells (53). Moreover, T cells in older adults exhibit hallmark features of immunosenescence, such as heightened inflammatory signaling and reduced Vδ–Jδ gene rearrangement, resulting in a contracted and less diverse TCR repertoire (53,54). Markers commonly used to identify senescent T cells include loss of expression of the co-stimulatory molecules CD28 and CD27 (55,56), together with increased expression of terminal differentiation markers such as CD57 and KLRG1 (5). In aged mice, the proportion of naïve CD4⁺ T cells declines to almost half of that observed in young mice, and the CD4⁺ compartment becomes increasingly heterogeneous with the accumulation of exhausted effector memory, cytotoxic CD4⁺ T cells, and activated Tregs (51,57). Aged CD4⁺ T cells exhibit diminished Ag responsiveness and impaired proliferative capacity (58,59). This leads to a reduced ability of T cells to produce IL-2, which, in turn, slows down the Ag-driven proliferation of B cells (60). In addition, peripheral naïve CD4⁺ T cells from aged mice exhibit an extended lifespan compared with those from young mice, a phenotype associated with decreased expression of the pro-apoptotic factor Bim and increased levels of the anti-apoptotic protein Bcl-2 (61). Several studies have reported prolonged survival of aged naïve CD4⁺ T cells, although findings have not been entirely consistent across models. For example, one study showed that T-cell subsets from older adults are more susceptible to apoptosis than those from young adults (62). Aged CD4⁺ T cells contribute to tissue inflammation, as genes typically upregulated under chronic inflammatory conditions, including Aw112010, S100a11, and Izumo1r, are highly expressed in the naïve CD4⁺ T cells of old mice (57). In CD3⁺ T cells of aged mice, methylation of the Foxp3 enhancer is reduced by approximately 26% compared with that in young controls, resulting in an increased number of Tregs, which suppress effector T-cell proliferation and activity through the downregulation of CD86 on DCs (63).

In contrast, CD8⁺ T cells are profoundly affected by aging. In human peripheral blood, the proportion of CD8⁺ T cells with high SA-β-gal activity increases, and this heightened activity correlates with reduced proliferative capacity (12). Furthermore, aging suppresses the generation of CD8⁺ tissue-resident memory T cells in non-lymphoid tissues as the apoptosis regulator BFAR expressed in aged CD8⁺ T cells inhibits JAK2 signaling, thereby limiting STAT1-mediated reprogramming (64). Collectively, age-associated changes in T cells, including shifts in dominant subsets and reduced Ag-specific reactivity, not only compromise host defense against infection but also increase susceptibility to cancer. T-cell aging therefore represents a central immunological challenge in older adults, with direct implications for preventive strategies and cancer immunotherapy. Future studies should focus on elucidating the molecular mechanisms that distinguish T-cell senescence from exhaustion and on developing interventions to restore or reprogram aged T cells.

B-cell aging and loss of humoral diversity

Aging has a wide range of effects on the differentiation, metabolism, and Ab-producing capacity of B cells. The persistent presence of commensal bacteria in the gut drives cellular senescence of germinal center B cells, leading to reduced IgA production and diversity as well as alterations in gut microbiota composition (65). Age-associated B cells (ABCs) are characterized by surface phenotypes, including the expression of CD11c, CD11b, and T-bet, and the loss of markers such as CD21, CD23, CD95, and CD43 in various combinations (7,66). In terms of metabolism, ABC exhibit reduced mitochondrial energy production, characterized by a marked decrease in oxidative phosphorylation upon activation, and the accumulation of mitochondrial ROS. These alterations impair Ab responses by inhibiting B cell differentiation into plasma cells through the suppression of Blimp-1 (67). Furthermore, B-cell receptor (BCR) repertoire diversity substantially declines with age and is accompanied by an increased incidence of stereotypic BCRs associated with chronic lymphocytic leukemia (68). An analysis of the bone marrow B-cell compartment revealed a two-fold reduction in pro-B cells and a three-fold reduction in pre-B cells in aged mice compared with that in young controls, which was attributed to the age-related downregulation of Igf1r, which is essential for the pro- to pre-B cell transition (69). In humans, the number of non-switched B cells, memory B cells, and plasma blasts is markedly decreased in individuals aged more than 70 years, which suggesting that insufficient differentiation into activated B-cell subsets contributes to the diminished Ab responses observed in the older adults (68). At the molecular level, aging B cells also show upregulated expression of c-Myc, implicating altered transcriptional regulation in their dysfunction (70).

ABCs have a distinct phenotype, characterized by decreased Ab production and marker expression, which may lead to impaired vaccine efficacy and increased infection risk in older adults. However, their precise clinical impact remains incompletely understood, underscoring the need for further studies to define therapeutic strategies targeting B-cell aging.

IMMUNOSENESCENCE AND CANCER

Senescent immune cells in the TME

Cancer progression in older adults is closely linked to immunosenescence, which weakens immune surveillance and impairs the elimination of transformed cells. In a recent study, when comparing the population of immune cells in the TME, it was confirmed that adult mice had a lower T cell population and a higher population of B cells than young mice, although the myeloid population was similar. In addition, the TME of adult mice was confirmed to have an excessive decrease in the expression of genes related to the Ag presentation pathway in B cells and macrophages (71). Compared to the normal TME, the aging TME involves more severe inflammation, immunosuppression, and impaired immune cell function, which promotes tumor development and, in turn, accelerates immunosenescence, creating a vicious cycle (Fig. 3) (13). Therefore, it is important to understand the functional changes and interactions of each immune cell in the aging TME of various cancer types.

Figure 3. Immunosenescence and immunosuppressive networks in the tumor microenvironment. Aged immune cells show diminished immunosurveillance and reinforce the immunosuppressive environment in the TME. Aged TAMs and MDSCs create an immunosuppressive microenvironment through increased expression of tumor-promoting genes and oxidized lipids, and SASP enhances these changes. The decreased cytotoxic function of CD8⁺ T cell and NK cell weakens their ability to eliminate tumors, while the increase in Treg and T_TAD cell exacerbates immunosuppression. Furthermore, the decreased Ab production and differentiation capacity of ABC lead to clonal ABC accumulation and tumor malignancy.

With aging, NK and CD8⁺ T cells, which are normally central to antitumor immunity, lose cytotoxic competence, whereas SASP mediators remodel the TME to promote chronic inflammation and tumor progression. For example, inhibition of the IL-6/STAT3 pathway induces senescence in hepatocellular carcinoma cells, and IL-6 blockade in acute liver injury reduces the risk of liver cancer (72,73). SASP-driven inflammation also enhances Treg activity, leading to increased secretion of TGF-β, which suppresses helper T-cell differentiation, inhibits CD8⁺ T-cell proliferation, reduces NK cytotoxicity, and impairs Ab production by B cells (74). Within the aging TME, exhausted T cells are reduced, while tumor-infiltrating, age-associated dysfunctional (T_TAD) CD8⁺ T cells (SLAMF6⁻ TIM-3⁻) accumulate, which is mediated by altered NK-DC-CD8⁺ T cell interactions. T_TAD cells are characterized by low granzyme B expression, elevated expression of γH2AX, a marker of DNA damage, and markedly reduced tumor-killing ability (31). Aging further drives a shift in NK subsets from CD56^bright to CD56^dim CD57⁺ cells (75), accompanied by reduced IFN-γ secretion, which limits Th1 polarization, macrophage activation, and leukocyte recruitment (36). Senescent neutrophils suppress CD8⁺ T-cell recruitment and activation through IL-6 secretion, which activates the JAK/STAT3 pathway to promote tumor growth, survival, invasion, and metastasis (76). Aged tumor-associated macrophages (TAMs) exhibit increased infiltration with age and upregulate the expression of tumor-promoting genes due to activation of the aberrant NF-κB pathway, promoting the growth of colon cancer cells (77). In addition, tissue-resident CX₃CR1^high alveolar macrophages suppress CTL activity and secrete VEGF to drive angiogenesis, thereby supporting KRAS-driven lung tumorigenesis (78).

Aging also alters adaptive immune surveillance. In older adult patients with breast cancer, CD8⁺ T cells display reduced CD28 expression and increased levels of immune checkpoint molecules, such as Tim-3 and TIGIT, both of which contribute to tumor initiation and progression (79). In animal models, Tregs gradually expand within secondary lymphoid organs with age, and their enhanced immunosuppressive activity promotes tumor development (57). ABCs of aged mice with lymphoma differentiate into age-associated clonal B cells by c-Myc activation and mutation, which exhibit a blunted immune response and become malignant, and early accumulation correlates with shortened lifespan (70).

Myeloid-derived suppressor cell (MDSCs) expansion and function

MDSCs exert potent immunosuppressive effects in the TME by inhibiting T-cell activity, inducing Tregs, secretion of inhibitory mediators, such as IL-10 and TGF-β (80). MDSCs disrupt tissue infiltration of immune cell by downregulation CD44 expression on T cells (81) and Ag cross-presentation by transferring oxidized lipids to DCs (82). In addition, MDSCs promote the expansion of other immunosuppressive cell types such as Tregs and TAMs via CCR5 ligands (83). In addition to immunosuppression, MDSCs promote tumor progression through non-immunological mechanisms, including the induction of angiogenesis, EMT, and pre-metastatic niche formation (84). In a recent study, MDSCs were found to attenuate CD8⁺ T cell proliferation and antitumor responses by activating the p53 signaling pathway via GPR84, in young mice (85). These results suggest that functional changes in MDSCs may have a more significant impact on the immune system and cancer in older adults, who already have compromised immune function. Therefore, it is important to investigate how MDSCs change in the TME of older adults and what correlations they have with cancer progression.

Immunosenescence drives the accumulation and functional reinforcement of MDSCs. Increased numbers of MDSCs have been observed in the blood of healthy older adults (86), and significantly higher MDSC ratio have been observed in older adults individuals with a history of cancer (87). Senescent stromal cell-derived SASPs were implicated in the accumulation of MDSCs, and IL-6 was particularly important in this, resulting in the promotion of tumor growth (88). Compared to young MDSCs, aged MDSCs showed increased expression of senescence markers p16^Ink4a p21^CIP, and significantly increased TNFR2 expression and STAT3 activation in aged MDSCs compared to young MDSCs. TNFR2 overexpression induced JNK hyperactivation in aged MDSCs, promoting their expansion (89). Furthermore, genes related to oxidative phosphorylation and fatty acid metabolism were highly expressed in aged MDSCs, while genes related to immune responses were downregulated (86). In terms of interaction with other immune cells, aged MDSCs suppress CD3/28-induced T cell proliferation more efficiently than young MDSCs and induce T cells to Th2, thereby significantly contributing to immunodeficiency (86). It is unclear whether all inherent immunosuppressive properties of MDSCs are enhanced or diminished in the TME of older adults. However, it has been confirmed that MDSCs are abundant in the aged TME and are linked to tumor promotion. Therefore, therapeutic research targeting MDSCs is essential for effective cancer treatment in older patients. Thus, defining the age-related pro-tumorigenic mechanisms of MDSCs is essential for developing effective therapeutic strategies for cancer in older patients.

Immune aging and therapeutic response in older cancer patients

The advent of immune checkpoint inhibitors (ICIs) and CAR T-cell therapy has transformed cancer treatment. However, their efficacy and safety in older adult patients remain areas of active investigation. The age-related decline in T-cell function and expansion capacity might reduce the efficacy of ICIs, whereas increased expression levels of KLRG1, Tim-3, and CD57 in aged T cells might contribute to ICIs resistance (90). Increased KLRG1 in tumor-infiltrating senescent T cells interacts with E-cadherin in tumor tissues, thereby reducing cytotoxic efficacy and contributing to immune evasion (91). Furthermore, soluble Tim-3 cleaved by ADAM10/17 induced increased expression of carcinoembryonic Ag-related cell adhesion molecule 1 within tumors, leading to dysfunction of tumor-infiltrating T cells and increased anti-PD-1 resistance (92). Furthermore, the accumulation of senescent CD8⁺ T cells is associated with resistance to anti-PD-1/L1 therapy in patients with advanced non-small cell lung cancer, independent of their chronological age (93). Clinical studies suggest that ICIs can provide meaningful benefits in older patients, although the risk of immune-related adverse events may be heightened because of preexisting inflammaging and comorbidities (94). In addition, in the TME, Tregs induce T cell senescence by causing ataxia-telangiectasia mutated protein (ATM)-related DNA damage through the MAPK signaling pathway, which increases ICI resistance. This was found to be reversed by combined use of ATM and MAPK signaling inhibition and anti-PD-L1 therapy (95).

Similarly, CAR T-cell therapy faces unique challenges in older adults because immunosenescence impairs the expansion and persistence of engineered T cells, potentially limiting therapeutic durability (96). The age-associated decline in NAD⁺ metabolism impairs CAR T-cell persistence and antitumor activity, linking metabolic immunosenescence to reduced therapeutic efficacy (97). Additionally, CAR T-cells expressing senescence markers showed similar target killing activity to cells that did not, but their target cell-dependent proliferation and cytotoxic cytokine production abilities were reduced (98). Strategies to improve outcomes include optimizing CAR T-cell manufacturing from aged T cells, combining CAR T-cell therapy with checkpoint blockade, and developing less toxic regimens tailored for older patients.

CONCLUSION AND PERSPECTIVES

Immunosenescence profoundly reshapes immune surveillance and tumor immunity by driving chronic inflammation, metabolic dysregulation, and the accumulation of senescent immune subsets. The resulting SASP-mediated inflammatory milieu promotes tumor progression and resistance to immune clearance. Several core mechanisms have been identified as major contributors to impaired antitumor immunity, including age-associated defects in NAD⁺ metabolism, chronic activation of IL-6/STAT3 signaling, reduced DC–mediated priming of T cells, and the accumulation of dysfunctional CD8⁺ T cell subsets, such as terminally differentiated effector memory cells. The age-associated dysfunction of macrophages, DCs, NK cells, neutrophils, and lymphocytes converges with the expansion of immunosuppressive MDSCs, establishing a tumor-promoting microenvironment. Consequently, immunosenescence not only accelerates tumor progression but also limits the efficacy of ICIs and CAR T-cell therapies in older patients.

These insights highlight immunosenescence itself as a therapeutically actionable target. Strategies aimed at counteracting immunosenescence—such as modulation of NAD⁺ metabolism, suppression of SASP signaling, metabolic reprogramming of aged immune cells, and selective targeting of senescent immune populations—represent promising avenues to enhance antitumor immunity. In this context, emerging senolytic approaches, including CAR T-cells engineered to eliminate senescent cells, extend the conceptual framework of immunotherapy beyond direct tumor targeting toward systemic immune rejuvenation. CAR T-cells that selectively eliminate cells expressing the urokinase plasminogen activator receptor, a senescence-associated protein, reversed functional declines in the aged gut, including improvements in barrier function and gut microbiota composition (99). Similarly, CAR T-cells targeting NK group 2 member D ligands effectively killed senescent cells, reversing aging phenotypes (100). Although senolytic CAR T-cell therapies have not yet been applied in oncology, they exemplify a paradigm in which rejuvenating the aged immune system may enhance cancer immunotherapy by restoring immune competence and limiting pro-tumorigenic inflammation.

Finally, understanding the molecular and metabolic mechanisms underlying immune aging offers new opportunities for restoring immune competence and improving antitumor efficacy in older patients. The integration of immunosenescence-associated biomarkers with senescence-targeted therapeutic strategies is crucial for optimizing the efficacy of cancer immunotherapy across the aging spectrum.

Abbreviations

ABC

age-associated B cell

ATM

ataxia-telangiectasia mutated protein

BCR

B-cell receptor

CAR

chimeric Ag receptor

DC

dendritic cell

EMT

epithelial-to-mesenchymal transition

EV

extracellular vesicle

HSC

hematopoietic stem cell

ICI

immune checkpoint inhibitor

MDSC

myeloid-derived suppressor cell

SA-β-gal

senescence-associated β-galactosidase

SASP

senescence-associated secretory phenotype

TAM

tumor-associated macrophage

TME

tumor microenvironment

T_TAD

tumor-infiltrating, age-associated dysfunctional