Health problems caused by population aging are among the great challenges the world is facing today. Nearly half of the global disease burden (92 diseases (including 35 cancers), accounting for 51.3%, 95% uncertainty interval, 48.5–53.9) is considered age-related (1). These include colorectal cancer, a solid tumor of the gastrointestinal tract with the third-highest incidence and second-highest mortality rate globally (2). Cancer morbidity and mortality rates are the highest in individuals over 50 years of age, suggesting that aging may play a significant role in cancer development and progression (3). Studies on the mechanisms of aging and tumor development have shown that some hallmarks of aging (including genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) promote oncogenesis and progression, whereas others have shown antagonistic (telomere attrition and stem cell exhaustion) or ambivalent effects (disabled macroautophagy and cellular senescence) on tumors (4). Therefore, the effects of aging on tumors need to be specifically explored at the systemic, microenvironmental, and cellular levels.

The immune system constitutes the body’s defensive barrier by monitoring, protecting, and eliminating threats (5). However, the interaction between adaptive and innate immune cells can lead to chronic inflammation and increase the likelihood of cancer development, and different types of infiltrating immune cells can have opposite effects on tumor prognosis (6). In addition, immune system function decreases with age, known as immunosenescence, which increases the risk of cancer and is a key player in cancer development (7). It was Roy Walford who first elucidated the link between immunity and aging and coined the term “immunosenescence,” which refers to increased immunogenetic diversification due to aging, leading to a progressive decrease in the recognition function of the immune system (8, 9). Immune aging is not simply a one-way process that leads to dysfunction and other harmful effects, but a dynamic balance between adaptation and maladaptation (10).

Changes in the immune senescence process will further complicate the immune features of the tumor microenvironment (TME) and may therefore have diverse impacts on tumor development and immunotherapy. The TME is composed of multiple types of immune cells, cancer-associated fibroblasts, endothelial cells, pericytes, various tissue-resident cell types, and extracellular matrix (ECM) (11). The complexity of the TME lies in the fact that immune cells are recruited to and infiltrate the TME through the action of cytokines and chemokines secreted from cancer cells to play an antitumor role, but simultaneously produce additional features of the TME that facilitate immunosuppression and limit antitumor immune responses (12–14). Particularly in colorectal cancer, slight alterations in the TME will trigger complex immunotherapy changes (15). Increasing evidence suggests that both innate and adaptive immune cells in the TME have a facilitative effect on tumor progression, while crosstalk with cancer cells enhances the recruitment of suppressive immune cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (16–18). In addition, a decrease in antitumor immune cell infiltration and function, together with the accumulation of immunosuppressive cells and upregulation of ligands that bind to inhibitory receptors on immune cells, may contribute to immune escape and consequently lead to poor immunotherapy results (19, 20).

Although remarkable research advancements have been made for both immunosenescence and the TME in the past decades, the impact of their interaction on different constituents and tumor progression remains to be further explored. This review focuses on the process of immunosenescence and the role of TME regulation. In addition, we discuss the impact of immunosenescence on tumor progression and immunotherapy. Finally, we describe future directions for limiting tumor progression by intervening in immunosenescence.

The process of immune aging involves three distinct but interrelated components, i.e., the immune organs, immune cells, and circulating factors (chemokines, cytokines, and other soluble molecules), which change during aging and produce corresponding effects ( Figure 1 ) (21). Immune system aging ultimately results in increased incidence of infectious diseases and mortality, reduced responsiveness to vaccines, accelerated aging of other organs, and increased risk of tumors (22–25) Immunosenescence is a complex and well-integrated process.

The aging of immune organs is the most noticeable change. For example, thymus function degenerates in nearly all species. Thymic involution begins in childhood and reaches its peak in adolescence. While excessive energy use is reduced in this process, age-related degeneration is detrimental to the organism (26, 27). During this process, thymus cells are gradually replaced by adipocytes, which results in a decrease in the proportion of undifferentiated T cells produced by the thymus (e.g., naïve T cells) and an increase in that of terminally differentiated cells (e.g., memory or depleted phenotypic T cells) (28). Such changes are also observed in neonates with early thyme resection, suggesting that they are a sign of immune deficiency (29). In conclusion, thymic degeneration is associated with the age-related immune decline and makes one prone to age-related diseases.

The key factors in promoting and mediating immunosenescence are alterations in circulating factors (chemokines, cytokines, and other soluble molecules). Immunosenescence causes the body to gradually enter an age-related pro-inflammatory state, while simultaneously, the body exerts anti-inflammatory effects through low-level, sterile chronic inflammation to adapt and remodel the immune system (30). During this process, senescent cells secrete inflammatory, extracellular modifying, and growth factors as signaling and acting molecules collectively referred to as the senescence-associated secretory phenotype (SASP) (31).

The SASP is expressed upon exposure to excessive stresses, such as repetitive cell division, oxidative stress, mitochondrial degradation, oncogene expression, and other stresses that cause DNA damage ( Figure 2 ) (32). As an inflammatory response, the regulation of SASP is strongly associated with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. As a classical DNA damage response pathway, the p38 MAPK pathway is activated by oxidative stress and DNA damage and regulates NF-κB through the p16^INK4A, p53, and DNA damage checkpoint kinase CHK1/CHK2 mechanisms, which in turn produce the SASP (33–37). Another DNA damage response-related pathway, the ATM/ATR pathway, is thought to mediate NF-κB action via the key molecule GATA4 to produce the SASP (38). In addition, the downregulation of DNase (DNase2/TREX1) expression in senescent cells leads to the accumulation of DNA in the cytoplasm, which in turn leads to abnormal cGAS-STING pathway activation and SASP production through IFN-mediated NF-κB activation (39). Another pathway validated to produce SASP via NF activation is regulated by IL-1α, which phosphorylates IRAK1 via IRAK4 after binding to the IL-1 receptor and eventually activates NF-κB (40). Another signaling molecule that can regulate SASP is NOTCH1, which acts synergistically with NF-κB by activating the NOTCH-JAG1 pathway to produce TGF-β to induce aging while inhibiting C/EBPβ (41). In recent years, JAK/STAT pathway activation by signaling molecules including phospholipase A2 receptor 1 (PLA2R1), tumor necrosis factor (TNF)-α, and interferon (IFN)-γ has been shown to also induce SASP production (42, 43). The SASP generated through multiple pathways will profoundly impact immune cell function and ultimately restructure the TME.

Alterations in immune cells are the most complex part of immune aging and produce direct effects. Such alterations are mainly due to two aspects: on the one hand, as mentioned above, the SASP plays a regulatory role in immune cell senescence, and on the other hand, hematopoietic stem cell (HSC) senescence is considered to be the basis of immunosenescence (44). Inflammation is a major factor in HSC aging, as inflammatory factors such as IL-1, IFNα/γ, and TNF-α drive HSC aging (45–47). Aging HSCs and immune cells differentiated from HSCs are increased in numbers and show increased inflammatory factor secretion, reduced self-renewal capacity, diminished homing effects, and reduced energy metabolism (44). Aging immune cells interact with soluble factors, including the SASP, in the TME to influence tumor progression and therapeutic efficacy, reflecting the impact of immunosenescence on cancer.

The TME consists of various components that can be classified into a non-cancerous cellular fraction, including fibroblasts, neurons, adipocytes, and immune cells (adaptive and innate), and a non-cellular fraction, including ECM, chemokines, growth factors, cytokines, and vesicles (48). According to the characteristics of each component, the TME can also be subdivided into tumor immune microenvironment, tumor biophysical microenvironment, tumor microbe microenvironment, etc. (49–51) We propose the term “immunosenescence microenvironment” as a new TME component to reflect the impact of senescent immune-related cells and signaling molecules in the TME on tumor development ( Table 1 ). By analyzing the individual components of the immunosenescent TME, we can more clearly the delineate the role of immunosenescence on tumor development.

The relationship between immunosenescence and antitumor therapy reflects the fact that there always are two sides to the same coin. On the one hand, for gastrointestinal solid tumors such as colorectal tumors, radiotherapy, chemotherapy, and immunotherapy are important antitumor treatments besides surgery; however, these treatments induce immune senescence, termed “treatment-induced immune senescence.”

Radiotherapy and chemotherapy can cause cancer-associated fibroblasts to expand in the TME and exacerbate the inflammatory state, leading to immune senescence (139). In addition, radiotherapy and chemotherapy can accelerate cellular senescence by directly causing DNA damage (140–142). Immunotherapies such as immune checkpoint inhibitors can also induce senescence in TME components by inducing increased production of senescence-related cytokines (143).

On the other hand, senescence can be exploited as a new target in antitumor therapies ( Table 2 ) (144, 145). This is explained by the fact that senescent cells continue to secrete SASP and lead to the presence of a pro-tumoral tumor microenvironment. Thus, senotherapy refers to the rational use of treatments that target senescent cells to fight tumors (146).

One senotherapeutic strategy is the removal of senescent cells by using anti-aging cell drugs that complement other antitumor therapies by mitigating the negative effects of treatment-induced senescence. Some drugs are used after senescence-inducing cancer therapies to target senescent tumor cells for clearance (147). BCL family inhibitors (e.g., ABT-737 and ABT-263) are representative of this class of drugs; they scavenge senescent cells by inhibiting the anti-apoptotic BCL protein family (148, 149). The tyrosine kinase inhibitor dasatinib combined with quercetin selectively kills senescent cells by inhibiting the pro-survival network that is upregulated in senescent cells (150). In addition, there are immunotherapeutic drugs and antibody-drug combinations that can similarly remove senescent cells and synergize with senescence-inducing antitumor treatments (151, 152). Engineered CAR-T cells targeting urokinase-type plasminogen activator receptor, a characteristic protein on the surface of senescent cells, can be used as a therapeutic modality to remove senescent cancer cells (153). Another senotherapeutic strategy is to induce senescence of tumor cells and then target them for elimination. The key to this strategy is to find corresponding drugs that can be targeted to induce tumor-cell senescence. For example, the DNA replication kinase CDC7 can selectively induce senescence in TP53-mutated hepatocellular carcinoma cells, which can subsequently be killed by mTOR signaling inhibitors (154). Mitigating the negative effects of the SASP is another senotherapeutic strategy. This approach is mainly based on the inhibition of SASP-producing pathways, such as the above-mentioned p38 MAPK, NF-κB, and JAK/STAT pathways (155, 156).

Other therapeutic approaches, such as the use of engineered tumor-targeting TCR-T cells or of photochemotherapy to increase immune cell infiltration, have been successful in countering the immunosenescent TME by enhancing antitumor immune efficacy (157, 158).These diverse therapeutic approaches combined can exert a more significant antitumor effect by targeting the immunosenescent environment from different angles.

Although the molecular biology of immunosenescence has been explored and therapeutic strategies for tumors have been optimized based on its action mechanisms, the timely identification of immunosenescent phenotypes is more clinically relevant, which provides an opportunity for early intervention (159, 160).

Since aging occurs in the immune system, accordingly, the type of biomarker that most readily comes to mind is the senescent phenotype of immune cells. Of these, both CD8⁺ TEMRA (CD45RA⁺CCR7^-CD28^-CD27^-) and CD4⁺ TEMRA are markers of immunosenescence, with increased proportions and absolute numbers in colorectal cancer patients, reflecting low value-added potential and anti-apoptotic properties (161, 162). However, these markers are cell surface receptors and must be assayed using flow cytometry, which requires fresh blood samples. In contrast, the soluble form of immunosenescence markers are more stable and can be measured from stored serum, making them promising candidates as soluble markers of immunosenescence. However, these markers are less specific, as they can also be detected during acute inflammation. The soluble markers sCD163, sCD28 and sCTLA-4 have great potential for application as biomarkers of immunosenescence (163–165). These soluble markers can be detected using ELISA methods, but further studies are needed to compare the diagnostic performance of these markers with the gold standard (cell surface receptor) assay. In addition, some mutations in genes associated with immunosenescence such as PIK3CA, TP53, NF-κB, AMPK, mTOR, and P53 may also serve as biomarkers of the aging process (166–169).

Immunosenescence, as a feature of this stage, increases the risk of infectious diseases and tumors while decreasing antitumor immune functions. This is because immune senescence results in changes in immune organs, immune cells, and the SASP, which all interact with each other. Such changes significantly impact solid tumors of the gastrointestinal tract, such as colorectal cancer, which have a complex TME, and ultimately lead to the formation of an immunosuppressive tumor immunosenescence microenvironment. In such an environment, immunosuppression is manifested in multiple aspects, including immunosuppressive cell recruitment, increased secretion of inhibitory cytokines, and diminished antitumor immune cell function. These changes allow the tumor to develop and deteriorate, and increase its tendency to invade, and affect antitumor therapy, which in itself induces immune senescence and induces immunosuppressive changes. Therefore, senotherapy, a new therapy targeting immune senescence, has been developed on the basis of various antitumor therapies to remove senescent tumor cells and restore the antitumor capacity of immune cells from a different perspective. However, more in-depth studies on the tumor immune senescence microenvironment need to be conducted to paint a more complete picture of immunosuppression and explore the mechanisms by which immunosenescence attenuates antitumor immunity. This will enable the development of antitumor drugs and different therapeutic strategies for aging characteristics. However, the therapeutic effects remain to be verified in long-term experiments.

TZ: Conceptualization, Investigation, Writing – original draft. RW: Conceptualization, Investigation, Methodology, Writing – original draft. HF: Conceptualization, Investigation, Writing – original draft. YY: Conceptualization, Formal Analysis, Writing – original draft. HJ: Data curation, Writing – original draft. ZP: Data curation, Writing – original draft. LZ: Investigation, Supervision, Writing – review & editing. GY: Funding acquisition, Supervision, Writing – review & editing. WZ: Funding acquisition, Project administration, Supervision, Writing – review & editing.