Immunosenescence, Physical Exercise, and their Implications in Tumor Immunity and Immunotherapy.

Introduction

The intricate relationship between the aging process and the concurrent decline in immune system efficacy has been extensively studied 1 - 3 . With the global population aging, it is essential to comprehend the mechanisms behind the age-related decline in immune function, known as immunosenescence. This understanding is crucial for tackling the rising incidence of age-associated diseases, including cancer. And the dynamic relationship among the immune response, physical activity, and the shifting paradigm of antitumor immunity is a major research hotspot at present 4 , 5 .

Immunosenescence is characterized by alterations in cellular composition and immune function, which result in attenuated reactions to pathogens and an increased susceptibility to various chronic conditions 1 , 6 . One such disease that prominently manifests with age is cancer, in which the compromised immune system contributes to the development and progression of malignant tumors 7 . Given the intricate relationship between aging and cancer, developing strategies for delaying immunosenescence and enhancing antitumor immunity is a prime focus of ongoing research.

Physical exercise, widely acknowledged for its multifaceted health benefits, has recently gained attention for its potential to modulate the immune system 8 . Numerous studies have demonstrated that regular exercise can positively affect immune function, attenuating the detrimental effects of immunosenescence 9 , 10 . The mechanistic basis of this positive effect involves the modulation of inflammatory mediators, enhancement of immune cell activity, and formation of an immune environment conducive to effective antitumor responses 11 , 12 .

In recent years, the field of tumor immunology has witnessed remarkable progress with the advent of immunotherapy 13 , 14 . Various types of cancer immunotherapies, such as immune checkpoint inhibitors (ICIs), adoptive cell transfer, cytokine treatments, oncolytic virus therapy and cancer vaccines, have emerged and demonstrated potential in clinical settings. Immunotherapy harnesses the body's innate immune system to selectively identify and eradicate cancer cells, representing a transformative strategy in cancer treatment 13 - 15 . Understanding the complex relationship among immunosenescence, physical exercise, and antitumor immunity is essential for optimizing the efficacy of immunotherapy, particularly in the context of an aging population.

This review provides a comprehensive summary of immunosenescence, the influence of physical activity upon immune system functionality, and the roles of these factors in shaping antitumor immunity, aiming to facilitate the development of innovative and personalized strategies for treating age-related diseases and improving the outcomes of immunotherapy.

Aging and the immune system

Immunosenescence, defined by the reduction in immune functionality as one ages, involves a multifaceted set of biological processes. This includes significant organ remodeling and diverse cellular regulatory mechanisms 2 . Senescent cells secrete a variety of factors known as the senescence-associated secretory phenotype (SASP), which not only promote chronic inflammation but also induce senescence in neighboring healthy cells. Simultaneously, this persistent inflammatory state accelerates immune cell senescence, impairing immune function and preventing the clearance of both senescent cells and pro-inflammatory mediators. This creates a vicious cycle of inflammation and cellular senescence. Prolonged inflammation in organs such as the lungs, liver, and bone marrow can hinder effective clearance, contributing to organ damage and the development of age-related pathologies 16 . Immunosenescence attenuates the ability of the immune system to induce effective responses against pathogens and vaccinations. Although the comprehensive landscape of underlying changes remains elusive, some notable alterations include dysfunction of hematopoietic stem cells, an altered naive-to-memory cell ratio within T and B cell populations, inflammaging, accumulation of senescent cells, weak responses to novel antigens, and altered stress responses 17 , 18 (Fig. 1 ).

Innate immune cells

Neutrophils

Neutrophils serve as the first line of defense against infections and are the most abundant circulating cells in human blood, rapidly recruited to injury sites 19 . Traditionally, it was believed that their inability to proliferate post-maturation leads to rapid exhaustion and a short half-life. This limited understanding suggested neutrophils had a narrow functional role in immune defense, unlike other myeloid cells. Recently, however, this view has been challenged. Studies indicate that neutrophils may survive in circulation for up to 5.4 days, and their lifespan can extend following activation. Additionally, neutrophils can undergo reverse transmigration from injury sites back into circulation, although the reasons for this phenomenon remain unclear. Evidence suggests that these recirculating neutrophils may enhance T cell proliferation and responses by migrating to lymphoid organs 20 .

Despite the preservation of neutrophil count in aged individuals, the functional abilities of these cells—such as chemotaxis, phagocytosis, and the production of NETs—deteriorate due to the aging process 21 , 22 . Studies investigating changes in the quantity and function of neutrophils in geriatric animal models are relatively limited. In a study by Nacionales et al. , transcriptomic analysis showed that geriatric mice with sepsis exhibited weaker neutrophil mobilization, phagocytosis, and chemotaxis than their younger counterparts 23 . Additionally, a decreased accuracy in chemotaxis, along with a compromised ability to clear apoptotic cells (efferocytosis) and generate immune responses, has been associated with a prolonged state of immunosuppression 24 . However, further investigation is warranted to elucidate the alterations in the count, phenotype, and function of neutrophils among elderly patients.

Monocytes/Macrophages

Tissue-resident macrophages originate from circulating monocytes and are tissue-specific. They defend against pathogens via phagocytosis and cytokine release, activating innate immunity 25 . They also present antigens to boost adaptive immunity 26 .

With advancing age, the overall count of macrophages within the body remains relatively stable; however, their function is remarkably altered. Macrophages can be categorized into two subsets as follows: M1, characterized by pro-inflammatory and anti-tumorigenic properties, and M2, characterized by anti-inflammatory and pro-tumorigenic properties 27 . The debate surrounding the occurrence of macrophages in a state of senescence within living organisms remains an area of contentious discussion and ongoing investigation in the field of biology. In the geriatric population, M1 macrophages are predominant in healthy hepatic and adipose tissues, whereas M2 macrophages, characterized by their immunosuppressive activity, are predominant in bone marrow, lymphoid, spleen, muscular, and pulmonary tissues 28 - 31 . Macrophages exhibiting M2-like characteristics have been shown to promote angiogenesis in geriatric mice with injury. This observation implies a correlation between senescent macrophages and the development of numerous age-associated disorders, with a particular emphasis on neoplastic conditions 32 .

Aging is associated with a marked decrease in macrophage phagocytic activity and a concomitant reduction in surface expression of Toll-like receptors (TLRs) 26 . The reduction in TLR expression levels has been associated with a concurrent rise in the proportion of regulatory T cells (Tregs) 33 . Evidences showed that macrophages from aged mice demonstrate reduced reactivity to TLR-1, TLR-2, and TLR-4. This attenuated response may be attributed to the decreased synthesis of important pro-inflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-α), owing to weakened activation of the NF-κB, p38, and JNK pathways 34 , 35 . Li et al. revealed that the phagocytic activity of macrophages is compromised, at least in part, owing to a reduction in the expression of Rac1 mRNA. This downregulation decreases the expression of Rac1-GTP and suppresses the activation of the Arp2/3 complex, resulting in decreased polymerization of F-actin, impaired formation of filopodia, and reduced surface expression of MARCO (a receptor crucial for the efficient engulfment of pathogens through phagocytosis) 36 .

Furthermore, the decline in the antigen-presenting capacity of macrophages to CD4 T lymphocytes has been linked to aging. This decline predominantly stems from the reduced expression of major histocompatibility complex class II (MHC-II) molecules, particularly the human leukocyte antigen (HLA)-DR isotype 37 . Efferocytosis, which refers to the phagocytic removal of apoptotic cells, has been shown to decline with age. The age-dependent decline in efferocytosis can impair the role of macrophages in the resolution of infections and modulation of inflammatory responses, consequently increasing the risk of tissue damage 38 . Accumulation of senescent tissue-resident macrophages and neutrophils has been shown to promote chronic, low-grade inflammation. This persistent inflammatory state contributes to immunosuppression mediated by macrophages, eventually driving the initiation of various diseases, including cancer 39 . In aged mice harboring neoplasms, the proportion of myeloid-derived suppressor cells (MDSCs) within the bone marrow, peripheral blood, and spleen is notably high. The increased abundance of MDSCs constitutes a critical barrier, as these cells are involved in mediating immunosuppression. Consequently, persistent immunosuppression not only impedes the removal of senescent cells but also prevents the destruction of tumor cells while disrupting tissue protein homeostasis and energy metabolism 40 . Cells characterized by the senescence-associated secretory phenotype (SASP) release various chemotactic and inflammatory mediators. Mediators such as chemokines and cytokines play a pivotal role in orchestrating the recruitment of MDSCs to the tumor microenvironment (TME). This recruitment process not only fosters immune evasion but also enhances metastatic potential, thus underscoring their significance in tumor progression and metastasis facilitation 40 . He et al. showed that MDSCs can modulate T-cell responses during the embryonic and fetal phases of development in mice and humans. Additionally, accumulation of MDSCs can indicate an underlying pathological condition or can be a physiological response to pregnancy 41 . Excessive proliferation of MDSCs has been shown to promote immunosenescence. An increased proportion of MDSCs can lead to detrimental secondary effects on tissue integrity. This outcome is primarily attributed to the cellular production of cytokines, including IL-10 and transforming growth factor beta (TGF-β), which influence tissue integrity and regulation of immune responses 42 .

Dendritic Cells

Dendritic cells (DCs) are essential antigen-presenting cells (APCs) that initiate adaptive immune responses by internalizing antigens and presenting them to T cells 43 . Activation occurs via pattern recognition receptors (PRRs) upon encountering pathogens, leading to increased expression of MHC class I and II molecules and co-stimulatory molecules like CD40, CD80, and CD86. This process also triggers the secretion of proinflammatory cytokines such as IFN-γ, TNF-α, IL-6, and IL-12, enhancing T-cell priming 43 , 44 . DCs are categorized into myeloid DCs (mDCs), which effectively present antigens and secrete cytokines, and plasmacytoid DCs (pDCs), which are key producers of type I IFN 43 , 45 .

Although a reduction in the number of DCs is commonly associated with aging, recent studies have suggested that, in some cases, the DC count is relatively stable or moderately increased in elderly individuals 46 . On the contrary, the functionality of DCs is substantially altered with advancing age 46 . Evidences showed that DCs obtained from elderly individuals had an enhanced proinflammatory profile characterized by elevated baseline synthesis of cytokines, including IL-6 and TNF-α. This inflammatory condition was potentially associated with SASP, a hallmark of immunosenescence 47 - 49 . Li et al. highlighted in their study that there exists diminished expression of costimulatory molecules among CD8α DCs isolated from aged mice. These molecules play a crucial role in facilitating interactions with MHC class II and CD40, pivotal for effective T-cell priming. This observed downregulation potentially hinders the capacity of DCs to elicit robust T-cell priming responses 50 . DCs from elderly individuals often exhibit a reduction in their quantity, HLA-DR expression, and functional efficiency, particularly in terms of migration, antigen presentation, pinocytosis, and phagocytosis 51 . Despite the important role of DCs in orchestrating immune responses, immunomodulatory therapies specifically targeting DCs are lacking. The cytokine FLT3L, known for its role in DC proliferation, has been shown to ameliorate immunosuppression triggered by sepsis 52 , 53 . In addition, IL-15 has been shown to exert efficient immunostimulatory and proliferation-inducing effects on DCs 54 .

MDSCs, which are associated with immunosenescence, can negatively affect the functionality of DCs 55 . Studies have shown that stimulation of MDSCs with lipopolysaccharides (LPSs) and IFN-γ can disrupt DC maturation DCs in mouse bone marrow cultures 56 . Additionally, DCs co-cultured with human MDSCs exhibit diminished antigen-presenting capabilities and suppressed cytokine synthesis 57 . TGF-β1 has been identified as an effective inhibitor of the maturation and functional activity of DCs in both humans and murine species 58 . The role of TGF-β1 in the mouse epidermis is pivotal for the development and maintenance of Langerhans cells, exhibiting variable effects across different subsets of DCs 59 . Therefore, MDSCs may inhibit the function of DCs, potentially resulting in the attenuation of T- and B-cell responses in inflammation and cancer.

Natural killer cells

Natural killer (NK) cells, a subset of lymphocytes, significantly bolster the adaptive immune system. Their pivotal function lies in stimulating both innate and adaptive immune reactions, particularly targeting cancer cells 60 . They can not only deliver a rapid, non-specific attack on cells hosting pathogens 61 but also relocate and facilitate prompt reactions by enhancing the function of myeloid lineage cells, notably macrophages, through the secretion of IFN-γ 60 , 61 . In human peripheral blood, NK cells are categorized into CD56bright and CD56dim subsets, distinguished by their differential expression of the homophilic adhesion molecule CD56. The former subtype is associated with cytokine production, whereas the latter is associated with cytotoxicity 62 .

The number of NK cells typically remains unaltered or exhibits a slight increase in elderly individuals 63 . This moderate increase can be attributed to the higher proportion of the mature CD56dim subtype and the lower proportion of the immature CD56bright subtype 64 . The IFN-γ production in NK cells either remains unaltered or potentially escalates as age progresses, however, their cytotoxic capacity is frequently reduced, possibly owing to the decreased secretion of perforin into the immunological synapse 65 , 66 . NK cells possess activating receptors such as NKp30, NKp46, and DNAM-1, which are important for the identification and elimination of different tumor cell types, including hematological cancer 67 , melanoma 68 , and ovarian cancer 69 cells. Researchers have hypothesized that alterations in the expression profiles of these receptors among older individuals could impact the capacity of NK cells in surveilling and eradicating malignant cells 70 , 71 . For older individuals who have been diagnosed with acute myeloid leukemia (AML), the NK cell population shows unique changes. This is manifested by a decrease in the generation of immature CD56 bright cells and a simultaneous increase in the generation of highly differentiated CD56 dim cells. These changes are suggestive of disease progression and function as prognostic indicators 72 - 74 . A clinical study that involved the infusion of killer cell immunoglobulin-like receptor (KIR) ligand-mismatched NK cells into elderly patients with AML after immunosuppressive chemotherapy validated the safety and applicability of NK cell transplantation within this specific patient group 75 .

Adaptive Immune Cells

B cells

B cells, derived from the bone marrow, are essential components of the adaptive immune system and crucial in coordinating both innate and adaptive immune responses 76 , 77 . They can identify a wide spectrum of antigens, encompassing proteins, lipids, polysaccharides, nucleic acids, and diverse chemicals. The precision of B cells in antigen recognition is substantially increased through their interaction with B-cell receptors (BCRs), and this process is further enhanced by the synergistic action of helper T cells 76 , 77 .

Upon receiving co-stimulatory signals, immature B lymphocytes undergo activation, followed by cell division and differentiation into plasma cells. These differentiated cells have the unique ability to synthesize highly specific antibodies. After an infection has been resolved, some plasma cells form memory B cells, which trigger a rapid and enhanced response to the same pathogen upon future encounters 78 . Furthermore, B cells, by producing antigen-specific immunoglobulins (Igs) and undergoing class switching, play a pivotal role in humoral immunity. They can also act as APCs, activating T cells by expressing MHC class II molecules 79 , 80 .

Advancing age is accompanied by a concurrent decline in both the number of B cells and the functional capacity of hematopoietic stem cells within the bone marrow 81 , 82 . Additionally, the circulatory levels of two vital growth factors, namely, a proliferation-inducing ligand (APRIL) and B-cell-activating factor (BAFF), are remarkably reduced in elderly individuals. The reduced expression of these factors in the plasma of older individuals correlates with a decline in B cell count, which is essential for maintaining mature B cells in peripheral blood 83 .

As age progresses, there is a decline in the functional capacity of B cells, resulting in diminished humoral immune responses and decreased antibody efficacy. The diminished functionality of cells leads to reduced antibody titers and diminished binding affinity. This outcome arises from the intricate interaction between intrinsic and extrinsic factors 84 . An important intrinsic factor is the decreased ability of B cells to form germinal centers, which affects somatic hypermutation and affinity maturation. This state is worsened by a decline in the expression of activation-induced cytidine deaminase (AID) due to the downregulation of the transcription factor E47. As a result, class switch recombination and affinity maturation are prevented 85 . The decline is contributed to by alterations in BCR signaling and reduced expression levels of costimulatory molecules, such as CD86 82 . Furthermore, the transformation of a significant portion of naive B cells into memory B cells poses limitations on the production of high-affinity antibodies against new antigens 86 .

The age-related decline in CD4+ T helper cell function, along with other extrinsic factors, plays a pivotal role in the regulation of B-cell function. While CD4+ T helper cells are crucial for germinal center formation, somatic hypermutation initiation, and high-affinity antibody synthesis in B cells, their effectiveness diminishes with age 87 , 88 . Altogether, the intrinsic and extrinsic changes in B-cell dynamics synergistically attenuate the humoral immune response in elderly individuals. Despite the integral role of B cells in coordinating immune responses, studies developing therapeutic strategies for modulating their activity are limited. A relevant study showed that androstenediol, a derivative of dehydroepiandrosterone (DHEA), enhanced B-cell responses in a murine model of aging 89 . This finding highlights the potential therapeutic value of DHEA-derived metabolites in regulating B-cell function 89 .

T cells

During immunosenescence, a notable inconsistency is observed between the unaltered total T cell count and the remarkable heterogeneity among T cell subpopulations throughout life. A hallmark characteristic of this diversity lies in the reduced fraction of naïve T cells, concomitant with an escalation in the fraction of highly differentiated CD28-negative memory T cells, often denoted as senescent T cells 90 . Upon encountering antigens, T cells experience proliferation and subsequently differentiate into a diverse array of effector T cell clones, each characterized by distinct functional attributes 91 . A specific subset of clones among these exhibits sustained specificity towards antigens, impacting both humoral and cell-mediated immune responses. The classification of T cells based on phenotype relies on the expression of distinct cell surface markers, primarily CD molecules, and the cytokines they secrete. T helper cells with CD4+ expression are categorized into Th1, Th2, Th17, and T follicular helper cells 91 , 92 . Th1 cells, which perform a vital function in combating intracellular pathogens, and Th2 cells, which safeguard against extracellular parasites and regulate inflammation through the secretion of cytokines including IL-4, IL-5, IL-6, and IL-13, have been implicated in autoimmune disorders 93 . Additionally, Th2 cells contribute to anti-inflammatory responses by secreting IL-10 and stimulate B cells to facilitate their maturation to memory and plasma cells 94 . CD8+ T cells, which exhibit cytotoxic activity and protect against intracellular pathogens, are classified as Tc1 and Tc2 subtypes based on their cytokine secretion profiles 95 , 96 . The diverse roles played by T cells in adaptive immunity emphasize the requirement of an in-depth investigation into individual T cell subtypes. Notable age-related changes have been reported in CD8+ T cells 3 . In particular, CD8+ T cells undergoing senescence exhibit a reduction in the expression of CD28 family receptors 97 . Conversely, there is a notable upregulation in the expression of immune biomarkers including CD57, TIM-3, KLRG-1, and CD45RA 98 - 100 . The augmented expression of inhibitory receptors on the surface of senescent T cells denotes a state of exhaustion, reminiscent of senescence yet governed by distinct mechanisms and characterized by unique features. 101 , 102 . In contrast to cellular exhaustion, cellular senescence is considered an irreversible process. Most of the existing research on T cell senescence focuses primarily on peripheral blood T cells, comprising a small fraction of the total T cell population 103 . Therefore, further investigation is imperative to advance comprehension of the mechanisms governing T cell senescence.

The interplay between metabolic and epigenetic factors emerges as a crucial determinant in regulating the differentiation pathways of T cells 3 , 104 . Initially, pre-T cell receptors (TCRs) are subject to genetic rearrangement in the thymus 105 . Following the antigen recognition by professional APCs, quiescent T cells undergo activation, characterized by their proliferation and differentiation into effector cells 106 , 107 . A hallmark alteration in T cells is the upregulation of aerobic glycolysis, driven by an increased expression of glucose transporters (GLUTs) on the cell surface. The escalation observed is attributed to the overexpression of genes associated with glycolysis, facilitated in a c-Myc-dependent fashion 108 . This metabolic change is accompanied by the activation of signaling cascades that contribute to the elevation of mitochondrial biogenesis and replication of mitochondrial DNA (mtDNA), which encodes factors essential for oxidative phosphorylation (OXPHOS). However, the precise underlying mechanisms remain unclear 109 . Studies have described a metabolic profile that reflects restructuring of the mitochondrial proteome, a phenomenon termed "one-carbon metabolism" 107 . In response to a viral challenge, naïve T cells rapidly multiply and diversify into specialized subsets that are important for the clearance of pathogens, destruction of infected cells, and overall management of infection 110 , 111 . Following the clearance of antigens, the predominant fate of activated T cells entails programmed cell death, known as apoptosis, with a minority transitioning into memory cells. 112 . Research indicates that CD28 interacts with various factors to activate the PI3K-PKB/AKT-mTOR signaling pathway, a critical process for TCR reorganization and the metabolic reprogramming of fatty acids, glutamine and glucose during T-cell maturation 113 , 114 . The mammalian target of rapamycin (mTOR) complexes, mTOR complex 1 (mTORC1) and mTORC2, serve as principal regulators of gene expression, each playing a unique role in the differentiation of T cells 115 . Continuous activation of mTORC1 expedites the transition of naïve T cells into CD8+ effector cells, while suppression of mTORC2 correlates with the generation of CD8+ memory T cells 116 . Senescence in T cells is characterized by a gradual transition toward a dysfunctional state, accompanied by alterations in systemic equilibrium and a general state of immunosuppression. This transition involves metabolic reprogramming and epigenetic changes, resulting in cellular aging and potential apoptosis 117 . Age-associated thymic atrophy impedes TCR rearrangements necessary for the production of double-positive thymocytes. The increased glycolytic activity of aging T cells can be partially attributed to variations in CD28 expression. During T cell aging, stress can lead to a failure to express essential components of the electron transport chain (ETC) and the subunits of OXPHOS 118 , leading to an increase in reactive oxygen species (ROS) levels; a decline in proteasomal function; and the subsequent suppression of mitochondrial biogenesis, one-carbon metabolism, and basal lipid metabolism 119 - 121 . In vivo , T cells in a senescent state exhibit a diminished expression of key functional molecules, including senescence-associated β-galactosidase (SA-β-gal), granzyme B (GZMB), and perforin, which are essential for cytotoxic activity 122 , 123 .

Stimulation of T cells initiates gene expression alterations that are important for driving their maturation to effector cells and maintaining their effector functions. This dynamic process is closely related to epigenetic changes. Enhancer-binding protein 4, a transiently expressed product of the c-Myc gene, serves as a crucial target of multiple molecules encoded by genes induced upon activation, playing an indispensable role in maintaining T-cell activation 124 . Effector function-associated genes are characterized by dynamic epigenetic modifications that enhance the precision and speed of their transcriptional responses to subsequent stimuli. This epigenetic imprint is preserved in human CD8+ memory T cells for an extended period and may be responsible for maintaining their effector functions 125 , 126 . T-cell differentiation is characterized by the deposition of methyl groups on the promoters of genes that are suppressed and the removal of these groups from the promoters of genes that are activated 127 . Studies employing chromatin immunoprecipitation have demonstrated that the simultaneous presence of the active mark, that is, trimethylation of histone H3 at lysine 4, and the repressive mark, that is, trimethylation of histone H3 at lysine 27, at promoter regions is a hallmark of the differentiation of naïve CD8+ T cells 128 . The degree of methylation and the extent of variation within the methylome strongly rely on the specific T cell subset, with senescent CD8+ T cells exhibiting more pronounced changes. Alterations in the global patterns of DNA methylation are considered one of the most definitive epigenetic modifications associated with senescence in T cells 129 . Usually, CpG islands within silent genes are hypermethylated and exhibit an accumulation of repressive histone modifications, whereas DNA sequences adjacent to CpG islands represent hypomethylated regions associated with senescence. Inversely correlated with the expression of genes associated with cellular immune responses and differentiation within CD8+ T cell subsets are the methylation statuses, particularly for CD27 and SATB1. This correlation suggests that epigenetic aging is linked to a reduction in T cell functionality 130 . Furthermore, in several studies, the rate of biological aging has been correlated with the degree of DNA methylation at particular CpG sites 131 . Additionally, various aging models have documented a decrease in the expression of fundamental histone proteins 132 . Senescent T cells are defined by unique patterns of chromatin condensation, termed senescence-associated heterochromatic foci (SAHF), along with increased chromatin accessibility and decreased expression of linker histone H1 133 , 134 . In combination with changes in histone modifications, hypomethylation, especially in repetitive genomic sequences situated within heterochromatic domains, could instigate genomic instability and precipitate early cellular senescence 135 , 136 . The decline in naïve T cell proportions with aging is notably correlated with a significant reduction in miR-92a expression within CD8+ T cells 130 . In senescent T cells with diminished CD28 expression, upregulation of miR-24 results in reduced expression of the histone variant H2AX, thereby impairing the cellular response to DNA damage 137 . Epigenetic modifications are crucial in driving T cell senescence and are similarly observed in the genomes of various other immune cells. Remarkably, T cells in a senescent state display epigenetic characteristics akin to those found in exhausted T cells. In a study, an in-depth analysis of tissues from different organs of mice revealed a clonal subset of CD8+ T cells expressing GZMK that exhibited a phenotype indicative of exhaustion 138 . The proportion of GZMK+CD8+ effector memory (EM) cells in human peripheral blood mononuclear cells (PBMCs) increases with age, with these cells sharing specific epigenetic changes and exhaustion markers with mouse GZMK+CD8+ T cells 138 . Basic leucine zipper ATF-like transcription factor, which is highly expressed in senescent CD8+ T cells, is crucial for differentiation leading to T-cell exhaustion 139 . Terminally exhausted T cells often display augmented chromatin accessibility within the promoters of effector genes such as GZMB and IFN-γ. This accessibility remains unaffected by aging, indicating that the mechanisms driving senescence and exhaustion share some common pathways 139 . In the natural aging process of mice, there is a progressive buildup of CD4+ T cells that exhibit a memory phenotype, characterized by the presence of the programmed cell death protein 1 (PD-1). These cells emerge as the predominant subpopulation of T cells as the mice advance in age. However, this process is markedly accelerated in mice with leukemia 140 . The expression of CD39 during aging results in a decreased proportion of CD4+ T cells 141 . In addition, accumulation of Tregs increases with age 142 - 144 , with the proportion of CD4+CD25+ Tregs in peripheral blood being higher in older mice 145 . Similarly, Treg infiltration is more pronounced and Foxp3 mRNA expression is higher in older Lewis lung cancer mouse models and older patients with lung cancer than their respective younger counterparts 146 , 147 .

Exercise and the immune system

Physical exercise can enhance immune function by alleviating the negative outcomes of aging, including immunosenescence and inflammaging, and obesity, including inflammation and immunosuppression 9 , 148 , 149 . In addition, physical exercise can induce notable alterations in both innate and adaptive immune systems (Fig. 1 ). The dual role of exercise in ameliorating immune dysfunction and reshaping immune responses highlights the complexity of physiological adaptations that occur in response to physical exertion.

Innate immune cells

Neutrophils

Engaging in a single session of physical exercise can substantially influence both the quantity and distribution of circulating neutrophils 150 . High-intensity resistance exercise has been shown to elevate neutrophil counts, which reach a 3-fold increase after exercise 151 - 153 . In addition, extended periods of endurance exercise, lasting from 0.5 to 3 hours, can lead to a 5-fold increase in neutrophil counts 154 . Although an increased count of neutrophils, along with that of other immune cells, is typically associated with infection and inflammation, it is noteworthy that immune cell counts induced by physical exercise usually revert to baseline levels within 6-24 hours after the cessation of exercise 155 .

Research examining the impact of physical activity on leukocytes, particularly neutrophils, has revealed that consistent exercise does not result in notable alterations in the peripheral blood leukocyte levels 156 . Studies focusing on endurance exercise have reported a notable reduction in neutrophil counts after therapeutic exercise sessions, particularly in individuals with chronic inflammatory conditions. In addition, this reduction has been associated with an increase in insulin sensitivity, body mass index (BMI), maximal oxygen consumption rate (VO2max), and fasting triglyceride levels 157 . Whether these changes are adverse or advantageous depends on the specific context. Notably, a study on resistance exercise showed that variations in the proportion of circulating neutrophils manifested more rapidly after a higher-volume/lower-intensity regimen (5 sets of 10 repetitions at 80% of one-repetition maximum, 1 RM) than after a lower-volume/higher-intensity regimen (15 repetitions at 100% of 1 RM) 158 . The reasons for the varying temporal responses of neutrophils to different exercise regimens remain unknown and warrant further investigation.

The initial increase in blood neutrophil counts after exercise is rapid and pronounced, with a subsequent, delayed increase occurring several hours after exercise. This dual-mode reaction has been associated with the extent and intensity of the physical exercise undertaken 155 , 159 . Neutrophilic leukocytosis observed promptly and subsequently after exercise is thought to be regulated by catecholamines and cortisol, respectively 160 . The ability of neutrophils to adhere to endothelial cells is an important early step in their translocation to sites of infection or trauma. However, studies have indicated that although intense, acute physical activity can enhance the chemotactic and phagocytic activities of neutrophils, it does not appear to increase their adherence to the endothelium 161 , 162 . A single session of intense exercise may attenuate the oxidative response and degranulation of neutrophils upon exposure to bacterial agents, an impact that can be sustained for a long duration. In addition, exercise can trigger an increase in the spontaneous phagocytic activity, degranulation, and oxidative burst potential of neutrophils 163 - 165 . Altogether, these findings suggest that acute physical exercise not only transiently decreases the responsiveness of neutrophils to environmental triggers but also facilitates the migration of highly active neutrophils into circulation and enhances their autonomous degranulation 166 . Although numerous studies have examined the effects of both acute and chronic exercise on neutrophils, the precise effects of exercise on the functionality of neutrophils warrant further investigation.

Monocytes/macrophages

Regular engagement in physical activity has been shown to reduce the baseline proportion of circulating inflammatory monocytes, particularly CD14lowCD16+ cells. Studies examining the impact of exercise through cross-sectional and longitudinal methodologies have consistently shown that participants engaging in physical exercise demonstrate a diminished proportion of inflammatory monocytes, concomitant with reduced TLR4 expression on cellular membranes and a mitigated inflammatory reaction to LPS stimulation. 167 - 169 . The precise mechanisms underlying the anti-inflammatory effects of exercise on tissue-resident monocytes remain elusive. However, preclinical studies on mouse models have shown that exercise can elicit inflammatory responses in peritoneal macrophages, suggesting that physical exercise has different effects on circulating and tissue-resident monocytes 170 - 172 . In addition, studies have shown that regular exercise can mitigate systemic inflammation in mice with high-fat diet-induced obesity 173 , 174 and reduce macrophage accumulation at sites of chronic inflammation 175 . These findings collectively validate the anti-inflammatory effects of regular physical activity.

After exercise, the proportion of circulating inflammatory monocytes transiently increases, typically reverting to pre-exercise levels during the recovery period 176 . This acute elevation, lasting approximately 2 hours, is thought to reflect the transfer of monocytes from the marginal pool to the blood 177 . Intense exercise preferentially stimulates the release of CD14+CD16+ monocytes, which produce stronger inflammatory responses than CD14+CD16- monocytes 178 , 179 . CD14+CD16+ cells, which are capable of tissue infiltration, are released from the endothelium in response to physical exertion. The proportion of CD14+CD16+ monocytes typically decreases as the body recovers, possibly owing to their recruitment to tissues or remarginalization 176 . Furthermore, the cytokine secretion profile of monocytes is altered after exercise, with a significant decrease being observed in the expression of IL-6, IL-1α, and TNF-α, potentially owing to the downregulation of TLR on monocytes 180 - 183 . A similar immediate increase in the proportion of circulating monocytes is observed after resistance training. Based on the intensity and duration of the workout, the cell count may revert to normal within 15-30 minutes after exercise or peak 120 minutes after the cessation of exercise 151 , 152 , 158 .

Given the low frequency of circulating macrophages and their primary maturation within tissues, studies investigating the relationship between acute exercise and macrophages in humans are limited. In the tumor microenvironment, macrophages are generally characterized by an M2 phenotype, which can inhibit the effect of chemotherapy and radiotherapy, and promote tumor growth and metastasis. Tumor-associated macrophages (TAMs) of the M2-like phenotype exhibit the most pronounced ability to internalize glucose within the tumor microenvironment. This elevated glucose uptake activates the hexosamine biosynthetic pathway, thereby catalyzing O-GlcNAcylation, which is essential for the enhancement of tumor dissemination and the development of chemotherapy resistance 184 . Engaging in physical activity has the potential to preferentially polarize TAM towards an M1 phenotype, which is associated with antitumor effects. This M1 polarization can enhance the immune response against tumors, promoting the destruction of cancer cells and limiting tumor progression. A sedentary lifestyle, in contrast, may promote the skewing of tumor-associated macrophages (TAMs) towards the M2 phenotype, thereby supporting tumor progression, enhancing local invasion, and fostering metastasis to distant organs. Recent studies indicate that TAM may not be strictly M2; instead, they could represent a more complex transition from M1 to M2 as tumors progress and trigger various molecular signaling pathways 185 . Initially, M1 macrophages may be polarized in early-stage tumors. As the tumor grows and becomes malignant, these M1 macrophages could subsequently shift towards an M2 phenotype, evolving into pro-tumor "tumor-educated" macrophages.

Regular engagement in aerobic exercise is known to foster a macrophage phenotype that is anti-inflammatory within the adipose tissue of obese individuals. However, this effect is abrogated upon the specific elimination of PPAR-γ in the myeloid lineage of murine models, underscoring the pivotal function of PPAR-γ in modulating the metabolic and phenotypic adaptations of macrophages in response to aerobic exercise regimens. Deficient in PPAR-γ within myeloid cells, slender mice display intensified pro-inflammatory traits 186 . An 8-week regimen of moderate aerobic exercise on a treadmill, characterized by continuous activity at 70% of maximum oxygen uptake (Vo2 max), elicits an anti-inflammatory profile specifically in adipose tissue-resident macrophages, without affecting the phenotype of peritoneal macrophages. This observation implies that the influence of aerobic exercise training on macrophage polarization and metabolic function is inflammation-level dependent and site-specific. A plausible mechanism by which such exercise modulates macrophage polarization is via the secretion of catecholamines 187 , 188 . Monocytes and macrophages alike exhibit adrenergic receptors (ARs) and are capable of responding to catecholaminergic stimulation. During physical activity, the secretion of adrenaline elicits immunomodulatory actions, enhancing the reactivity of pro-inflammatory macrophages in healthy individuals and triggering an anti-inflammatory profile in those with elevated baseline inflammatory levels. Nevertheless, the underlying molecular pathways responsible for these immunomodulatory effects remain to be fully elucidated. Animal studies have shown that sustained exercise can reduce the antigen-presenting ability of macrophages and downregulate MHC II molecules on their surface 189 , 190 . Acute exercise can significantly enhance the phagocytic activity, nitrogen metabolism, chemotaxis, antitumor activity, and ROS levels of both M1 and M2 macrophages 191 , 192 . In addition, exercise can promote the polarization of adipose tissue-resident macrophages from the M1 to the M2 phenotype in mice, improving muscle adaptation and reducing body fat percentage. This finding indicates that increasing the proportion of M2 macrophages in adipose and muscle tissues may yield therapeutic benefits in cancer 193 .

Studies have shown that immunotherapy can regulate macrophage polarization. TAMs abundantly express both PD-1 and PD-L1, and the involvement of the PD-1/PD-L1 pathway in TAM-driven tumor immune evasion has been comprehensively demonstrated 194 . Hartley et al. discovered that PD-L1 consistently sends inhibitory signals to TAMs, leading to the development of an immunosuppressive M2 phenotype in these cells 194 . A separate study focusing on colon cancer showed that PD-1 has an immunosuppressive effect on TAMs by changing their phenotype and functions, potentially promoting a shift towards a tumor-promoting (M2) phenotype. Within the context of TAM alterations influenced by the tumor microenvironment, polarization has been identified as a crucial factor in the development of cancer, as it dictates the characteristics and activities of TAMs within this environment 195 .

The effect of exercise and immunotherapy on macrophage polarization is a complex process involving multiple signaling pathways and molecular mechanisms. Exercise combined with immunotherapy may enhance the therapeutic effect by modulating the polarization of TAMs. For example, exercise can promote the transformation of M2-TAM to M1 phenotype, while inhibition of SHP2 can block CD47-SIRPa pathway, restore phagocytic activity of M1 macrophages, repolarization TAM to M1 phenotype, restore its phagocytic function, promote CTLs infiltration in tumors, lead to immunostimulating TME, and significantly inhibit tumor growth 196 .

The relationship between physical activity and macrophage dynamics within the tumor microenvironment remains ambiguous, particularly regarding whether regular exercise or training reduces the infiltration of macrophages into tumors. Understanding the nuances of this phenotypic transformation and its implications for the TME is crucial and necessitates further research. Investigating how different types of physical activity influence macrophage polarization and activity could uncover new therapeutic strategies to enhance antitumor immunity and improve outcomes for cancer patients. This area of study holds promise for elucidating the complex interactions between lifestyle factors and immune responses in the context of cancer 197 .

Dendritic cells

A single session of dynamic exercise can lead to an increase in the production of monocyte-derived DCs in healthy adults; however, the functional consequences of this effect remain unclear 198 . The post-exercise increase in the number of circulating DCs may not always result in a heightened inflammatory response 199 , 200 . Preclinical studies have shown that consistent exercise can lead to a pronounced increase in the mixed leukocyte reaction, the surface expression of MHC II molecules, and the production of IL-12 by DCs. However, no significant differences are observed in the expression of costimulatory molecules, such as CD80 and CD86, on DCs before and after exercise 201 , 202 . Aerobic exercise may preferentially activate pDCs, which produce IFNs to counteract viral and bacterial infections, and enhance immune surveillance through the selective stimulation of pDCs 203 . Despite these findings, the effects of exercise on DCs remain elusive, necessitating further investigation.

NK Cells

NK cells have emerged as a major research hotspot in the field of exercise immunology owing to their notable modifiability by physical activity and the relative simplicity of their examination 204 , 205 . Multiple studies have validated the effects of exercise on both functionality and abundance of NK cells; however, the findings remain controversial. Similar to other leukocytes, NK cells are swiftly released into the bloodstream following acute physical exercise. This release is enhanced by catecholamines' effects on adhesion molecules and the consequent rise in shear stress 204 - 206 . NK cells preferentially adhere to human endothelial cells (EC). Catecholamines, acting through β2-ARs, are capable of facilitating the mobilization of NK cells from the marginating reservoir to the circulating compartment. This process is mediated by altering the adhesive interactions between NK cells and EC. However, protracted periods of exercise may lead to a decrease in the proportion of circulating NK cells owing to their migration to tissues or their remarginalization 204 , 205 . High-intensity resistance training, involving 60-100% of one-repetition maximum (1 RM) across various volumes, can result in a transient increase in NK cell counts, with this increase lasting up to 15 minutes after exercise 151 , 152 . Additionally, the proportion of CD16+/CD56+ NK cells reverts to the baseline level within 3 hours after a session of sustained aerobic exercise 153 .

Variations in the proportion of CD16+/CD56+ NK cells have been positively associated with the intensity and extent of the physical activity undertaken. Notably, in contrast to other lymphocyte subsets, CD16+/CD56+ NK cells remain unaltered after low-intensity resistance training 207 . NK cells are characterized by their innate cytotoxic activity, which involves the secretion of IFN-γ and promotion of apoptosis in infected or transformed cells. The cytotoxic potential of NK cells is an important measure of their functional status 208 . Early-stage and cross-sectional studies have indicated that a session of moderate-intensity exercise can enhance the cytotoxic activity of NK cells 209 , 210 , which typically decreases as the body enters the recovery phase 211 . These fluctuations in cytotoxic activity can be primarily attributed to changes in the relative frequency of NK cells in the PBMC population. Both high- and moderate-intensity exercises have been associated with notable changes in the proportion of circulating NK cells, which can markedly affect the interpretation of NK cell cytotoxicity assessment 211 . However, studies employing multiple target tumor cells (e.g., K562) to examine the impact of exercise on the cytotoxic activity of NK cells have proposed an alternative perspective 212 . In particular, these studies have suggested that exercise leads to selective re-distribution of NK cell subsets exhibiting a mature phenotype, which augments their cytotoxic activity against targets expressing HLA 212 , 213 . Consequently, the nature of the changes observed in NK cell functionality in the context of exercise remains ambiguous. Whether these changes are exclusively indicative of variations in the quantity and distribution of NK cell subpopulations induced by exercise or whether exercise affects the intrinsic functionality of individual NK cells remains unclear.

Adaptive Immune Cells

B Cells

The effects of physical exercise on humoral immunity, specifically the functionality of Igs, have been evaluated by measuring Ig levels in both mucosal and systemic environments. Studies investigating the impact of exercise, whether short- or long-term, on Igs have shown that systemic Ig concentrations are either moderately increased or remain unchanged in response to physical exertion 214 , 215 . The mucosal immune system protects the mucous membranes in the respiratory, nasal, and gastrointestinal tracts. This protective effect is mediated by the secretion of secretory immunoglobulin A (SIgA) by specialized plasma cells. SIgA is strategically positioned to identify and neutralize pathogens that threaten the mucosal barriers, thereby serving as the first line of defense against pathogen invasion 216 , 217 . Extensive efforts have been directed towards understanding how physical activity influences the concentration of sIgA in saliva 218 . Studies have demonstrated that the structured program of an exercise regimen and the intensity and duration of the exercise are key factors affecting the concentration of sIgA 8 , 219 . Elevation in salivary sIgA levels signifies bolstered immune functionality and correlates with reduced susceptibility to upper respiratory tract infections (URTIs) among those embracing an active physical regimen. On the contrary, a significant temporary decrease in salivary SIgA levels can increase susceptibility to URTIs 220 , 221 . Although earlier studies have shown that athletes participating in endurance activities have a decreased salivary concentration of sIgA, especially during rigorous training 221 - 223 , several recent studies have indicated that the salivary concentration of SIgA in athletes is usually similar to that in non-athletes, except under conditions of high-intensity exercise 224 , 225 . The post-exercise decrease in salivary sIgA levels is attributed to the diminished inhibitory effect of the parasympathetic nervous system to some extent 219 . Consequently, moderate-intensity exercise sessions have a negligible impact on the expression of Igs in plasma cells, whereas prolonged and vigorous exercise can decrease the salivary concentration of SIgA. The number of B cells, which are crucial for Ig synthesis, may slightly increase during and immediately after exercise based on the duration and intensity of the exercise. However, the increased B cell count typically decreases below the pre-exercise level during the initial stages of recovery and returns to the baseline level within a day 155 , 226 . Consistently, studies have reported a higher proportion of circulating B cells during or after high-intensity resistance training, with the effects persisting after a 3-hour recovery period and across various volumes of training sessions performed at 60-100% of 1 RM 153 , 227 , 228 . Additionally, low-intensity resistance training has been shown to increase the proportion of circulating B cells 229 . It is noteworthy that physical exercise of different intensities can induce acute lymphocytosis, either during or immediately after the activity. In-depth research is warranted to understand the impact of physical exercise of various intensities on B cell counts in the bloodstream and to elucidate the influence of exercise regimens on the functional aspects of B cells.

T Cells

Numerous studies have shown that T cell proliferation is suppressed after physical exertion 4 , 8 . In athletes who undergo high-intensity training, the functionality of T cells, particularly circulating Th1 cells, is highly sensitive to increased training volumes. Protracted periods of intense training decrease the proportion of circulating Th1 cells, compromising their functionality. However, lymphocytosis is common, marked by an increase in T cell counts during and immediately after exercise, followed by a decline below the baseline level in the early recovery phase 230 , 231 . Modulation of T cell counts in response to various exercise regimens usually relies on the intensity and extent of the physical activity undertaken 230 , 231 .

Regarding resistance training, the post-exercise response of CD4+ T cells varies among different study cohorts. The number of CD4+ T cells increases immediately after high-intensity resistance training 151 , 152 , 227 and within 1 hour after low-intensity resistance training 232 . It typically reverts to the pre-exercise level within 30 minutes after high-intensity exercise 152 but remains high for up to 1 hour after low-intensity exercise 232 . Despite an overall increase in total lymphocyte counts, no significant changes in CD4+ T cell counts are observed before and after moderate-intensity resistance training (60-70% of 1 RM across various volumes) 153 . In the resting phase (>24 hours after the last training session), the proportion of circulating lymphocytes, encompassing all T cell types, in athletes is usually comparable to that in non-athletes 233 .

Similar to the number of CD4+ T cells, that of CD8+ T cells transiently increases after high-intensity resistance training (aligning with intensities of 60-70% of 1 RM), reverting to the baseline level within the first 15 minutes of the recovery period or decreasing below the baseline level within the first 30 minutes of the resting phase. Complete restoration of CD8+ T cell counts is usually achieved within 3 hours after the cessation of exercise 152 , 153 , 227 . Low-intensity resistance training has been shown to induce an increase in the proportion of CD8+ T cells, which begins during the initial phase of the activity and persists for up to 60 minutes after exercise. The increased proportion of CD8+ T cells tends to normalize and return to the pre-exercise level within 20-60 minutes after the cessation of exercise 232 . Differences in exercise regimens and the timing of post-exercise blood sampling may account for the inconsistency in CD8+ T cell counts across studies. While the precise impact of physical exercise on T cell proliferation, both during and post-exercise, remains elusive, it is evident that exercise instigates alterations in T cell behavior. Therefore, in-depth studies are warranted to understand the correlation between the number and function of T cells in the context of different exercise regimens.

Exercise modulation of immunosenescence and anti-tumor immunity

Immunosenescence and cancer

The incidence of malignant neoplasms increases with age. This positive correlation is governed by two mechanisms as follows: progressive accumulation of genetic aberrations and immunosenescence, which is a key factor in carcinogenesis (Fig. 2 ). The geriatric population has been shown to have an increased risk of developing neoplasms 234 . In a study, a meticulous assessment of mammary epithelial cells from women aged between 16 and 91 years demonstrated that the age-related progressive accumulation of luminal and stem cells significantly increased the risk of malignant tumors 235 . This finding highlights the close relationship between aging, cellular behavior, and the risk of cancer.

In the complex and dynamic TME, various factors can induce a state of senescence in immune cells, leading to the impairment of cellular function. The role of immunosenescence in tumors is complex, involving various factors such as cAMP, glucose competition, and oncogenic stress within the tumor microenvironment. These factors can lead to the senescence of T cells, macrophages, natural killer cells, and dendritic cells 1 . In the geriatric population, immune dysfunction not only contributes to the initiation of tumors but also accelerates the aging of T cells. Immune system disorder in TME is characterized by an increased proportion of tumor-associated macrophages and Tregs 236 - 238 . Under hypoxic conditions, tumor cells exhibit an endogenous elevation in cyclic adenosine monophosphate (cAMP) levels, which serves as an intrinsic factor facilitating T cell senescence by attenuating the functionality of tumor-specific effector T cells 239 , 240 . Furthermore, tumor cells can initiate the PKA-CREB and P38 signaling pathways by generating cAMP, consequently leading to DNA damage and triggering T cell senescence 40 , 236 , 241 , 242 . Competition for glucose can induce DNA damage via the ATM pathway, triggering activation of the ERK1/2 and P38 pathways. This collaborative effect with STAT1/3 ultimately halts the T cell cycle, leading to senescence. Glucose-induced activation of the ATM and AMPK pathways promotes DNA damage, driving T cell senescence. AMPK further amplifies P38 activation by interacting with TAB1 protein, while concurrently suppressing the expression of the telomerase reverse transcriptase gene 18 , 243 . P38 has been shown to impede cell cycle progression by activating P53, P21, and P16 18 . T cells undergoing senescence increasingly rely on anaerobic glycolysis as their primary source of energy. This metabolic shift can lead to mitochondrial dysfunction and consequently increase ROS production 242 , 244 . Furthermore, the NFκB, C/EBPβ, and cGAS-STING signaling pathways have been shown to play an important role in T cell senescence 3 , 90 . Tumor cell stimulation via TLR8 activation has been demonstrated to bolster antitumor immunity through dual mechanisms: hindering senescence advancement in both senescent T cells and tumor-specific ones, thereby alleviating their immunosuppressive influence, both in vitro and in vivo 242 .

Multiple preclinical and clinical studies ( NCT04924374 , NCT05807243 , NCT04772092 ) have investigated the consequences of immunosenescence. Preliminary findings suggest that immunosenescence, particularly its impact on CD8 T cells, plays a crucial role in the development and management of breast cancer 245 . Studies using murine models of breast cancer have reported a decline in IFN signaling in CD8 T cells of older animals 246 . The senescent cellular environment is closely related to tumor metastasis and invasion, with T cell metabolism in TME exhibiting age-related changes. Compared with younger patients with melanoma, older patients exhibit more pronounced ECM alterations owing to changes in hyaluronan and proteoglycan link protein 1 (HAPLN1), which can enhance the invasiveness and metastatic potential of melanoma cells 247 . Additionally, the age-dependent increase in the secretion of sFRP2 by fibroblasts has been associated with enhanced angiogenesis and metastasis in melanoma 248 . Notably, senescence can have beneficial effects on the outcome of cancer. In several mouse models of tumors, including MC38, B16, and 4T1, a slower rate of tumor growth has been observed in older mice 249 . Elderly individuals with bronchial cancer have been shown to have reduced tumor velocity and metastasis, possibly owing to host factors associated with aging that may limit the proliferation and spread of aggressive tumor cells 250 . Similarly, older individuals with Engelbreth-Holm-Swarm cancer and B16F10 melanoma mouse models have been shown to have decreased tumor growth and metastasis along with increased survival rates 251 , 252 . A historical review of 1869 breast cancer cases reported a higher incidence of invasive ductal carcinoma in patients aged <39 years 253 . Moreover, recent research has demonstrated an increase in serum methylmalonic acid levels among elderly individuals, resulting in the upregulation of SOX4 expression. This molecular event may trigger transcriptional reprogramming, consequently enhancing the aggressiveness of cancer cells 254 . These diverse findings collectively emphasize the complex relationship between aging and cancer development.

The influence of chemotherapy on senescence of CD8 T cells in breast cancer has been demonstrated 245 . In a preclinical pancreatic ductal adenocarcinoma model, T/P drug treatment has been shown to induce senescence in pancreatic tumor cells and initiate the formation of a SASP, which is important for vascular restructuring. The process not only enhances the efficacy of chemotherapy by improving its uptake and potency but also promotes the infiltration of T cells into malignant tissues 255 . These findings suggest a correlation between the initiation and advancement of cancer and immunosenescence.

Effects of exercise on immunosenescence

Several studies have emphasized the positive influence of an active lifestyle on immunosenescence, focusing on both innate and adaptive immune components 9 , 10 (Fig. 3 ). Cross-sectional studies have consistently demonstrated that older adults with increased levels of physical fitness experience more health benefits than those with a less active lifestyle. A strong correlation is observed between regular physical exercise and the increased activity of NK cells in elderly individuals 256 . Additionally, the chemotactic activity of neutrophils in response to IL-8 is high in physically active, healthy elderly individuals 257 . Interventional studies have further delineated the impact of exercise on important aspects of innate immunity. Notably, the proportion of proinflammatory and senescent nonclassical CD14+/CD16+ monocytes increases after a 12-week program involving moderate-intensity strength and endurance training 167 . In the context of rheumatoid arthritis, high-intensity interval training has been shown to increase the oxidative burst and phagocytic activity of neutrophils 258 . These findings collectively indicate that regular physical activity can enhance innate immune responses, potentially decreasing the risk of infections and alleviating inflammation.

Although the response of an aging innate immune system to physical exercise remains to be elucidated, numerous studies have examined the effects of physical exercise on the adaptive immune system, with a special focus on T cells. An early cross-sectional study showed that mitogen-induced T cell proliferation was more pronounced in highly trained older women than in less trained older women 256 . Another study reported that elderly runners with an average of 17 years of training had improved T cell proliferation, which was associated with enhanced adaptive immunity 259 . Additionally, a study on healthy, non-competitive adults aged between 55 and 79 years demonstrated that these individuals exhibited minimal indicators of immunosenescence, with their thymic function markers being comparable to those in younger individuals. These physically active individuals exhibited lower levels of systemic inflammation and Th17 cell differentiation, with no significant differences being observed in the proportion of naïve T cells and regulatory B cells between them and their peers with a sedentary lifestyle. However, the proportion of senescent CD28-CD57+ T cells was found to be similar between active and inactive older adults 260 . The study reveals a significant correlation between cardiovascular endurance and the occurrence of senescent T cells within the circulatory system. This finding suggests that elevated levels of peak oxygen uptake are linked to a reduction in the percentage of senescent T cells and an augmentation in the proportion of naïve CD8+ T cells 258 . This relationship remains significant after accounting for variables such as age, BMI, and body fat percentage. However, when adjusted for VO2max values, the correlation between age and the proportion of senescent T cells is non-significant, indicating that cardiovascular fitness may significantly influence T cell dynamics related to aging 261 . Minuzzi et al. examined 19 master athletes aged >40 years with extensive training backgrounds. They found a decreased proportion of senescent central memory (CM) CD8+ T cells, senescent EM CD8+ T cells, and senescent CM CD4+ T cells in these athletes when compared with inactive individuals 28 . Additionally, the athletes had a decreased proportion of highly differentiated EM-like T cells across both CD4+ and CD8+ subsets 262 . Based on these findings, Minuzzi et al. proposed that regular exercise may not only prevent the accumulation of the aforementioned cell types but also promote their clearance through processes such as apoptosis 263 . A subsequent study showed that intense, acute exercise sessions primarily induced apoptosis in T cells exhibiting a senescent phenotype, thus validating the aforementioned hypothesis 264 . Furthermore, there is consistent evidence from cross-sectional studies indicating that routine physical activity has the potential to avert age-associated alterations in lymphocyte subgroups and partially ameliorate the decline in T cell functionality that occurs with aging.

Findings from cross-sectional studies have been tested and validated to varying extents through controlled exercise-based interventions. For instance, a study involving overweight postmenopausal women aged 50-75 years did not observe any changes in T cell proliferation after a 12-month aerobic exercise regimen 265 . Similarly, another study showed that a 32-week exercise regimen integrating endurance and strength training did not lead to an increase in T cell proliferation in older adults 266 . On the contrary, consistent endurance training has been shown to have positive effects on the CD4+-to-CD8+ T cell ratio in elderly individuals 150 . In individuals with prediabetes, a 3-week endurance training program has been shown to increase the proportion of naïve and CM T cells while decreasing the proportion of senescent EMRA CD8+ T cells 267 . Various factors can affect these results, including the type of exercise undertaken, which may have an impact on immunosenescence. In particular, endurance training has more positive effects than strength training 268 , 269 . The initial health status of participants may also serve as a contributing factor. Although many studies have focused on sedentary but overall healthy older individuals, the findings have indicated that individuals characterized by a "healthy risk" profile or identified as having an increased risk of immunosenescence (elevated IRP) may gain more advantages from regular physical activity. For example, sustained aerobic training has been shown to improve T cell proliferation in postmenopausal women after successful breast cancer treatment 270 . Additionally, individuals with prediabetes who have a diminished health status or specific conditions that elevate their IRP may be more likely to experience a reduction in the signs of immunosenescence through engagement in regular exercise. However, further research is warranted to clarify the specific types of exercise that are effective, understand the relationship between exercise frequency and response, and examine the efficacy of physical activity in restoring immune function.

The influence of physical activity on key health metrics has been extensively investigated, with multiple studies highlighting its effects on the response to vaccination. A study showed that men aged 65-85 years who had maintained a routine of physical activity for approximately 25 years exhibited more robust antibody reactions to influenza vaccines than their less active age-matched counterparts. Mechanistically, sustaining thymic function and preserving a pool of naïve T cells played an important role in delaying immunosenescence 271 . Another study showed that an exercise regimen performed thrice weekly at a moderate intensity over 10 months led to a significant increase in antibody titers after influenza vaccination 272 . In addition, older women who engage in regular physical activity have been shown to have higher antibody production in response to the Flu B vaccine when compared with their less active age-matched peers, with the response remaining elevated 18 months after the vaccination 273 . The relationship between exercise and immunosenescence has been examined in the context of various diseases, including cancer. Given that many patients with cancer present with an elevated risk of immunosenescence (IRP) and an active lifestyle is known to decrease the risk of cancer and yield better therapeutic outcomes, it can be hypothesized that some advantages of regular physical exercise are attributable to its effects on delaying immunosenescene 274 .

Effects of exercise on anti-tumor immunity

Immunosenescence remarkably increases the risk of cancer in elderly individuals, characterized by alterations such as decreased NK cell function, increased inflammation, compromised antigen processing by monocytes and DCs, accumulation of dysfunctional senescent cells, and reduced proportion of naive T cells capable of preventing the emergence of cancer cells. However, physical activity has been shown to delay the onset of immunosenescence. It enhances NK cell activity, strengthens antigen presentation mechanisms, attenuates inflammatory responses, and limits the accumulation of senescent cells, potentially serving as a preventive measure against immunosenescence-induced malignancies 12 , 275 .

With regard to the effects of physical activity on immune responses, NK cells exhibit the highest sensitivity to exercise-induced changes, followed by T cells, whereas B cells exhibit the least responsiveness 231 . NK cells, which are notably affected in the earliest stage of exercise, play an essential role in the innate immune system, whereas T cells are important for orchestrating the adaptive immune response. The rapid response of NK cells to exercise is attributed to their inherent reactivity and activation of specific receptors, including NKG2D and H60a, and the NKR-P1B receptor complex ligand Clr-b 276 - 278 . Pedersen et al. showed that adrenaline-mediated NK cell mobilization significantly increased immune cell infiltration, which prevents cancer growth, in mouse models 279 . On the contrary, inhibition of NK cell mobilization by the β-adrenergic receptor antagonist propranolol has been shown to promote cancer growth and reduce immune cell infiltration in tumors, indicating that adrenergic signaling may serve as a target for immune cell mobilization-dependent cancer suppression. Additionally, the targeted regulation of cancer cell metabolism may enhance anti-cancer immunity 280 , 281 . Integration of physical exercise with anti-cancer treatment strategies has been shown to enhance the mobilization and activation of NK cells, improve blood circulation, and promote cancer cell apoptosis, which can increase the core temperature of the body 205 . In addition, physical exercise exerts anti-inflammatory effects by reducing adipose tissue and increasing the number of anti-inflammatory Tregs, thereby alleviating systemic inflammation, promoting the release of anti-inflammatory cytokines 282 , and suppressing pro-inflammatory cytokines during muscle activity 283 . Both acute and chronic physical activity can induce cytokine responses that activate immune cells within the TME, leading to varied effects on cancer growth. The immunophenotypic landscape of the TME is dynamic and is significantly influenced by fluctuations in cytokine levels 197 .

In a study, acute physical activity was found to substantially increase the number of apoptotic lymphocytes in peripheral blood during a systemic immune response. Simultaneously, the proportion of senescent and memory T cells, including both CD4+ and CD8+ subpopulations, was remarkably increased 284 . Long-term engagement in physical activity has been shown to increase CD28 and T lymphocyte levels in both younger and older individuals 284 . Recent studies have indicated that moderate-intensity physical exercise does not influence the concentration of anti-inflammatory cytokines but may increase the levels of pro-inflammatory cytokines and enhance antigen-specific immune responses. These enhanced immune responses are associated with a decreased likelihood of developing cancer. On the contrary, high-intensity physical exercise can inhibit T cell proliferation and attenuate cytotoxic responses to specific antigens. Moreover, there exists a correlation with elevated levels of inflammatory cytokines and an augmented proportion of CD4+CD25+ Tregs, potentially heightening susceptibility to infections 285 . Although high-intensity exercise may not represent the optimal approach to preventing cancer development, moderate-intensity exercise has shown efficacy in impeding the progression of neoplastic diseases.

Altogether, physical activity can enhance immune cell mobilization and infiltration in the TME through the recruitment of NK cells, induction of cytokine-mediated anti-inflammatory responses, and amplification of T cell proliferation. These protective effects play an instrumental role in suppressing the proliferation of cancer cells and delaying the onset of immunosenescence.

Immunosenescence and immunotherapy

ICIs

ICIs are a class of monoclonal antibodies that can neutralize the suppressive impact of immunoregulatory proteins on the immune responses of effector cells. In clinical settings, ICIs are used to target PD-1 and CTLA-4 owing to the established function of these checkpoints in suppressing T cell activation and proliferation. Although age is not considered a primary prognostic factor in patients receiving ICIs, selection bias is evident owing to the under-representation of older individuals in clinical trials despite the high prevalence of cancer among them. On the contrary, older patients have been shown to have lower progression-free survival (PFS) and overall survival (OS) rates than younger patients in the CheckMate-017 trial for NSCLC, CheckMate-025 trial for RCC, Keynote-045 and 052 trials for urothelial carcinoma (as monotherapy), CheckMate-067 trial for melanoma, CheckMate-214 trial for RCC, and CheckMate-227 trial for NSCLC (which involved anti-PD-1/PD-L1-based combination therapies).

Recent studies have suggested a relationship between immunosenescence and decreased effectiveness of immune checkpoint blockade (ICB) (Table. 1 ). The pre-treatment proportion of senescent T cells may help predict treatment outcomes. Ferrara et al. identified a senescent immune phenotype (SIP) in CD8 T cells characterized by the loss of CD28 and the expression of CD57 and KLRG1 in patients with advanced NSCLC 286 . An elevated systemic immune-inflammation index (SIP) before treatment, specifically >39.5%, has been associated with low PFS and OS rates in patients undergoing ICB therapy. This association is evidenced by the decreased rate of objective response to ICB, a trend that is not observed in patients undergoing chemotherapy. T cells in these patients have a decreased proliferation rate and increased secretion of inflammatory cytokines, without a discernible relationship with the age or chemotherapy history of the patients. In patients with melanoma receiving ipilimumab, a higher baseline proportion of differentiated EM CD8 T cells has been associated with a lower OS rate 287 . Similarly, in patients treated with pembrolizumab, either alone or in combination with a lower dose of ipilimumab, a higher pre-treatment proportion of CD27-CD28-Tim-3+CD57+ T cells has been associated with a lower OS rate 288 . Although non-senescent T cells are considered indispensable for effective ICB, further research is warranted to examine the effects of T cell senescence on the efficacy of ICB.

SASP is a hallmark of cellular aging characterized by an increase in the serum levels of pro-inflammatory cytokines, including IL-1, IL-6, IL-8, and TNFα. Given that these cytokines play an important role in promoting tumorigenesis, SASP may be associated with decreased efficacy of ICB. For example, IL-6 can interfere with the activation of T cells by monocyte-derived DCs in the TME 289 and is associated with higher C-reactive protein levels and poorer outcomes in patients undergoing ICB therapy 290 . IL-1 can induce the production of CXCL1, CXCL2, and CXCL5 in intra-tumoral macrophages and monocytes, leading to the recruitment of neutrophils and MDSCs that can suppress antitumor immunity 291 . Additionally, IL-8 contributes to unfavorable responses to ICB, particularly by facilitating the recruitment of neutrophils and myeloid cells and by promoting immune evasion mechanisms involving NETs 292 .

The relationship between inflammaging and the efficacy of ICB therapy remains unclear 281 . Studies have suggested that pro-inflammatory SASP has positive effects on treatment outcomes, especially in cases in which chemotherapy or radiation therapy induces a state similar to senescence 293 , 294 . In melanoma characterized by dense immune cell infiltration, tumor cells can upregulate SASP-related genes, potentially leading to resistance to anti-PD-1 treatment 295 . However, some studies have revealed contrasting results. In lung adenocarcinoma, a senescence-associated gene expression pattern has been associated with a reduction in OS and is thought to be associated with SASP owing to the increased levels of IL-1α, IL-1β, IL-6, and VEGF 296 . Secretion of IL-6 by senescent osteoblasts can promote the formation of a microenvironment conducive to bone tumor growth 297 . Additionally, IL-6 secreted by tumor-resident senescent stromal cells can enhance MDSC infiltration and decrease the efficacy of anti-tumor T cell responses 298 . The complexity and discrepancies among the findings of existing studies pose a significant challenge to understanding the relationship between inflammaging and the outcomes of ICB therapy.

Adoptive T cell therapy

Chimeric antigen receptor (CAR)-T cell therapy is a well-known immunotherapeutic strategy for cancer. It involves the ex vivo genetic modification of patient-derived T cells to produce receptors that are capable of identifying specific antigens. These cells are expanded ex vivo and are reintroduced into the patient to selectively target and destroy cancer cells 299 . A major advantage of CAR over traditional TCRs is its ability to detect tumor-associated antigens without the requirement of HLA compatibility, which expands the range of target antigens.

Clinical studies have validated the therapeutic efficacy and safety of CAR-T cell therapy, particularly in hematological cancers. The FDA has approved the use of CAR-T cell therapy for the treatment of acute lymphoblastic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and multiple myeloma that are refractory or have relapsed 300 - 302 . Additionally, the benefits of CAR-T cell therapy have been observed in elderly individuals with hematological cancers. At present, multiple clinical trials are investigating the efficacy of CAR-T cell therapy in solid tumors, including but not limited to ovarian cancer, HER2-positive breast cancer, EGFR-positive biliary tract cancer, gastric cancer, pancreatic cancer, hepatocellular carcinoma, and colorectal cancer 303 .

Senescent T cells are present throughout CAR-T cell therapy. In the cell collection stage, patients with diffuse large B-cell lymphoma (DLBCL) who are non-responsive to anti-CD19 CAR-T cell therapy exhibit a higher proportion of CD28-CD27-CD3 T cells in leukapheresis samples 298 . Additionally, the proportion of senescent-like CD8+CD28-CD57+CD39+ T cells is found to be increased in CAR-T cells obtained from patients with refractory or relapsed DLBCL and AML 304 . After infusion, BCMA-CAR-T cells potentially acquire a senescent phenotype characterized by the expression of KLRG1 and CD57 in patients with multiple myeloma; however, the correlation with treatment efficacy remains unclear 305 . Therefore, evaluating T cell senescence is crucial for understanding the resistance mechanisms associated with CAR-T cell therapy.

The immunosuppressive microenvironment of solid tumors may impede the efficacy of CAR-T cell therapy 306 . The use of CAR-T cell therapy for treating solid tumors is challenging owing to the presence of an unfavorable TME, the risk of on-tumor/off-tumor toxicity, and low antigen specificity 307 . A promising strategy to overcome these challenges is the combined administration of CAR-T cells and histone deacetylase inhibitors (HDACis). Ali et al. showed that treatment of mice with pancreatic cancer with panobinostat, an HDACi, enhanced the antitumor efficacy of CAR-T cells by driving their maturation to CM cells, thereby enhancing the epigenetic accessibility of genes related to T cell memory 308 . The use of HDACis to catalyze the phenotypic transition of endogenous T cells toward a more durable memory phenotype may have beneficial effects in cases with pronounced T cell senescence.

NK cell therapies

Owing to their diverse immune functions, NK cells are gaining recognition as a promising option for cellular immunotherapy 309 . The therapeutic application of NK cells has shown encouraging results in the management of hematological cancers and after organ transplantation in clinical settings 310 . Evaluating the safety and potential side effects of chemotherapy in older individuals with AML, which has a higher prevalence among elderly individuals, is a topic of considerable interest. The susceptibility of elderly patients to the toxic effects of chemotherapy substantially challenges the treatment. Therefore, using NK cell-based immunotherapy in this age group represents a promising therapeutic approach. A recent clinical study ( NCT00540956 ) examined the post-chemotherapy recovery of NK cell function in elderly patients with AML who had achieved first remission, providing insights into the influence of chemotherapy on NK cells. Another clinical study ( NCT00799799 ) validated the feasibility and safety of using KIR-ligand-mismatched NK cells in elderly patients with AML who had undergone immunosuppressive chemotherapy, highlighting the therapeutic potential of NK cells in this population 75 . The use of KIR-ligand-mismatched haploidentical NK cells as a consolidation therapy after the first complete remission has been associated with prolonged disease-free survival in elderly patients with AML, especially when a large number of NK cells is infused 311 .

Exercise and immunotherapy

Immune checkpoint inhibitors

Recent studies on animal models have provided insights into the potential synergistic benefits of physical exercise and anti-PD-1 therapy. Wennerberg et al. demonstrated that integration of 30 minutes of treadmill activity daily with PD-1 blockade and radiation therapies significantly reduced the proportion of tumor-infiltrating MDSCs in breast cancer. This reduction was accompanied by increased CD8+ T cell infiltration, which effectively transformed the immunosuppressive TME into an environment more conducive to effector cell activity. Consequently, the group engaged in physical activity exhibited a pronounced decrease in tumor growth when compared with the sedentary group that received equivalent anti-PD-1/radiation therapy 312 .

In a study using a patient-derived xenograft (PDX) model of non-small-cell lung cancer, the synergistic effect of physical activity and PD-1 blockade was found to impede tumorigenesis. The suppression of tumor development was characterized by a decreased rate of tumor cell proliferation and an enlargement of regions undergoing tumor necrosis 313 . These findings emphasize the potential of exercise in regulating the immune system, notably by restricting myeloid cell infiltration in the TME. Consistently, another study showed that voluntary wheel running prevented the aggregation of MDSCs in breast cancer 314 .

The proliferation of polymorphonuclear MDSCs, monocytic MDSCs, and other immunosuppressive myeloid cells has a detrimental impact on the efficacy of immunotherapy 315 - 317 . Regular physical activity may enhance the efficacy of ICIs by negating the destructive effects of these myeloid cells. Paradoxically, sedentariness and/or obesity have been associated with a more favorable response to ICIs in both preclinical and clinical studies, with individuals with a higher BMI demonstrating superior therapeutic responses 318 , 319 .

Donnelly et al. highlighted the requirement of a meticulous investigation into the effects of BMI on treatment outcomes. Specifically, factors such as age, sex, cancer staging, lactate dehydrogenase levels, performance status, and BRAF mutation status should be considered when examining the relationship between BMI and ICB 320 . Although preliminary findings related to the relationship between exercise and ICB therapy are encouraging, considering the aforementioned factors is crucial when investigating the supplementary role of exercise in ICB therapy. Additionally, further research is warranted to elucidate the underlying mechanisms and maximize the therapeutic potential of physical exercise when integrated with immunotherapeutic approaches (Table. 2 ).

Adoptive T cell therapy

Owing to its biological impact on T cell dynamics, physical exercise has the potential to be integrated with adoptive T cell therapy. For instance, the rapid increase in the peripheral blood T cell count after acute physical activity can be strategically used to facilitate T cell collection during leukapheresis. This approach may circumvent production barriers such as low yields from patients with lymphopenia, extended durations of T cell cultures, and suboptimal ex vivo T cell proliferation 321 - 323 .

Acute exercise may trigger a biphasic immune cell response, with a temporary decline in cell counts after exercise, which indicates the protective redistribution of immune cells to different organs in response to stress 219 , 324 . The functionality of these redistributed cells is often enhanced, and if collected before their re-entry into tissues, they may represent a more effective population for therapeutic production, reducing the culture duration required to reach the optimal cell count for therapeutic dosage. Notably, preliminary findings suggest a correlation between shorter culture periods and the increased antitumor efficacy of CAR-T cells 325 . Additionally, short-term physical activity can increase the recruitment of less prevalent T cell subtypes, including γδ T cells, T cells with specificity for viruses, and T cells that target specific antigens.

The success of T cell therapy relies on the proliferation and longevity of T cells in vivo 325 - 327 . Physical activity can enhance the proliferation and survival of T cells by stimulating the secretion of IL-7 and IL-15, which are crucial for T cell expansion and sustenance, from skeletal muscle. Therefore, physical activity may increase the effectiveness of T cell-based immunotherapies. Interleukins, specifically IL-15 and IL-7, have been identified as crucial factors contributing to the increased efficacy of CAR-T cell therapy in preclinical settings. These cytokines remarkably enhance the proliferative ability, functionality, migratory behavior, and OS of CAR-T cells, increasing their efficacy in preventing neoplastic growth 328 . In the treatment of advanced lymphoma with CAR-T cell therapy, higher serum levels of IL-15 have been associated with an increase in the number of CAR-T cells and the rate of remission 329 . However, a recent study reported a decrease in T cell counts after intense exercise in animal models, indicating the suppression of hematopoiesis 330 . Therefore, further research is warranted to evaluate the potential adverse effects of physical exercise on T cell counts in patients with cancer.

Regular physical exercise may play an instrumental role in sustaining the optimal concentrations of IL-7 and IL-15, which are crucial for the proliferation and survival of T cells after adoptive transfer 331 , 332 . In particular, post-therapeutic physical activity may enhance the mobilization and distribution of the transfused T cells throughout the body. Sustained engagement in physical activity has been shown to ameliorate the age-dependent decline in immune function, which may in turn increase the effectiveness of immunotherapeutic interventions. Physical activity enhances immune function by maintaining a high proportion of naïve T cells, reducing the accumulation of senescent T cells, and increasing the proportion of stem-cell-like memory T cells. These changes are relevant to the preparation phase of T cells in clinical studies involving adoptive cell transfer (ACT) or CAR-T cell therapy 333 .

The relationship identified between VO2max levels and the proportion of naive CD8+ T cells indicates that long-term physical activity can enhance the defense capabilities of immune cells 261 , 334 . This enhanced immune response is evidenced by the increased frequency of immune cells that are known for their high reactivity and readiness to initiate a strong immune response. The underlying mechanism may involve the exercise-induced release of specific cytokines from skeletal muscle tissues. Notably, IL-7 and IL-15 are common cytokines that are secreted after physical exertion and play a crucial role in modulating the immune response. This cytokine-mediated pathway may serve as an important factor contributing to the efficacy of physical activity in triggering effective cellular defense responses. Altogether, physical exercise holds substantial promise in immune-related clinical interventions owing to its beneficial effects on the immune system.

NK cell therapy

The therapeutic efficacy of NK cells in cancer exhibits variability, which can be attributed to several factors. Notably, challenges associated with cell production, including low yields of NK cells from leukapheresis samples and suboptimal ex vivo cell expansion or activation, significantly contribute to this variability. After infusion, the persistence of NK cells and their ability to proliferate in vivo are crucial determinants of treatment outcomes in patients 335 .

Acute physical activity before leukapheresis may help overcome the abovementioned challenges. Post-exercise leukapheresis samples contain approximately 5-10 times more activated NK cells than samples obtained through conventional methods. Additionally, exercise has been shown to counteract the negative effects of obesity on NK cell functionality. Obesity can impair NK cell function by disrupting glycolysis, a process mediated by the mTOR pathway, owing to the excessive accumulation of lipids and fatty acids 336 , 337 .

Glycolysis and OXPHOS play an important role in optimal NK cell activation, which is initiated by cytokines such as IL-2, IL-12, and IL-15 338 . Specifically, IL-2 and IL-15 can upregulate metabolic regulators such as mTORC1 and c-Myc, which play an essential role in sustaining the viability of NK cells and enhancing their antitumor activity 339 , 340 . Given that regular physical exercise can decrease fatty acid levels in individuals with obesity or a sedentary lifestyle, it may improve NK cell function by mitigating the immunosuppressive effects of obesity 341 , 342 .

Discussion and Prospects

This review highlights the intricate relationship between immunosenescence, physical exercise, and anti-tumor immunity, with significant implications for aging-related diseases and cancer treatment. While the current understanding of these interactions is substantial, several key areas warrant further investigation to fully unlock the potential of exercise as a modulator of immune function and an enhancer of anti-tumor responses.

1. Mechanistic elucidation of exercise-induced immune changes: The exact mechanisms by which exercise modulates immune cell function and influences immunosenescence remain incompletely understood. Further research is needed to elucidate the signaling pathways and molecular mediators involved in exercise-induced immune changes. Specifically, the role of cytokines, such as IL-7, IL-15, and sIgA, in regulating immune cell proliferation, differentiation, and survival deserves further investigation. Additionally, the epigenetic mechanisms underlying exercise-induced changes in immune cell function and senescence need to be explored to identify potential therapeutic targets.

2. Personalized exercise interventions: The optimal exercise regimen for enhancing immune function and delaying immunosenescence remains unclear. Future studies should explore the individualized effects of different types, durations, and intensities of exercise on immune cell subsets and functional markers. This knowledge can inform the development of personalized exercise interventions tailored to the specific needs of individuals, including the elderly and cancer patients.

3. Integration of exercise with immunotherapies: The potential synergistic effects of exercise with immunotherapies, such as ICIs, adoptive T cell therapy, and NK cell therapy, warrant further investigation. Preclinical and clinical studies are needed to assess the combined efficacy and safety of exercise and immunotherapies in treating cancer. This research can also explore the optimal timing and duration of exercise interventions to maximize therapeutic outcomes.

4. Understanding the impact of comorbidities and lifestyle factors: The impact of comorbidities, such as obesity, diabetes, and cardiovascular disease, on the immune response to exercise and its potential influence on cancer development and treatment outcomes needs to be better understood. Additionally, the interplay between exercise, diet, and sleep, which are all important lifestyle factors, deserves further investigation to optimize immune function and improve health outcomes.

5. Longitudinal studies and population-based research: Longitudinal studies are necessary to track the long-term effects of exercise on immune function and its relationship with the development and progression of cancer. Population-based research can also provide valuable insights into the prevalence and correlates of immunosenescence in different populations, as well as the impact of lifestyle factors, including exercise, on immune health.

6. Development of novel therapeutic strategies: The findings from this review provide a strong foundation for the development of novel therapeutic strategies targeting immunosenescence and enhancing anti-tumor immunity. For example, drugs that mimic the effects of exercise on immune cells, such as those that increase IL-7 or IL-15 production, could be developed. Additionally, interventions that promote the clearance of senescent cells or improve the function of exhausted T cells could be explored.

There is an increasing agreement that exercise provides significant benefits for individuals following a cancer diagnosis. The 2018 Physical Activity Guidelines for Americans (PAGA) indicate that exercise positively impacts cause-specific mortality rates for prostate, breast, and colorectal cancers, as well as enhances quality of life and fitness for all cancer survivors 343 . There is biological evidence of an immune-stimulating effect in the hours after strenuous exercise. However, some other questions regarding specific exercise modalities remain open, such as the potential effects of resistance exercise on anticancer immune function 344 .

Different types of exercise have distinct effects on the immune system. Depending on the intensity, duration, and frequency of exercise, it can produce both short-term and long-term effects on immune function. Generally speaking, moderate aerobic exercise is considered beneficial for the immune system, while prolonged high-intensity exercise may lead to temporary suppression of immune function. Moderate aerobic exercises, such as walking, jogging, swimming, or cycling, are commonly regarded as enhancing the immune system's defense capabilities. Research shows that regular moderate-intensity exercise can boost the activity of immune cells, including natural killer (NK) cells, macrophages, and lymphocytes, which play key roles in fighting pathogens and tumor cells 345 . Studies indicate that after prolonged high-intensity exercise, NK cell numbers decrease, T cell function is temporarily suppressed, and pro-inflammatory cytokines like IL-6 increase, exacerbating inflammation. This immune suppression response is thought to be a protective mechanism for the body to repair physiological stress and damage caused by exercise 346 . Strength training and resistance training have more complex effects on the immune system. On one hand, moderate strength training can enhance immune function, similar to aerobic exercise, by promoting immune cell activity. On the other hand, excessive strength training, especially without adequate recovery, may lead to immune suppression and an increased risk of infections 331 . Therefore, maintaining a balanced exercise routine, with proper intensity and recovery time, can optimize the positive effects of exercise on the immune system and support overall health.

In conclusion, the relationship between immunosenescence, physical exercise, and anti-tumor immunity is complex and multifaceted. Further research is needed to fully understand these interactions and develop evidence-based strategies to optimize immune function, delay immunosenescence, and improve the outcomes of cancer treatment.

We thank Figdraw (www.figdraw.com) for expert assistance in the pattern drawing. The authors thank professional English editor (Bullet Edits) for assistance in improving the quality of language.

Funding

This work was also supported by a Research Foundation of Shanghai Artemed Hospital (Grant NO: ATM2022YJ01) to Dr. Wenge Li, a National Natural Science Foundation of China (NSFC) (Grant NO: 82203629) and a Shanghai Pujiang Program (Grant NO: 22PJD054) to Dr. Qi Wu, and a National Natural Science Foundation of China (NSFC) grant (Grant NO: 82303284) to Dr. Bei Li.

Author contributions

QW, SS and WL performed and conceived the review. XY and WP wrote the manuscript. XY, WP and BL drew all the figures. QW, SS and WL assisted in improving the quality of language. All authors read and approved the final manuscript.

Abbreviations

activation-induced cytidine deaminase

acute myeloid leukemia

antigen-presenting cells

a proliferation-inducing ligand

B-cell-activating factor

B-cell receptors

body mass index

cyclic adenosine monophosphate

chimeric antigen receptor

classic DCs

dendritic cells

diffuse large B-cell lymphoma

effector memory

glucose transporters

granzyme B

human leukocyte antigen

Immune checkpoint inhibitors

interferon gamma

immunoglobulins

interleukin

killer cell immunoglobulin-like receptor

lipopolysaccharides

myeloid DCs

myeloid-derived suppressor cells

major histocompatibility complex class II

mitochondrial DNA

mammalian target of rapamycin

mTOR complex 1

neutrophil extracellular traps

natural killer

overall survival

oxidative phosphorylation

peripheral blood mononuclear cells

plasmacytoid DCs

patient-derived xenograft

progression-free survival

pattern recognition receptors

senescence-associated heterochromatic foci

senescence-associated secretory phenotype

senescence-associated β-galactosidase

secretory immunoglobulin A

systemic immune-inflammation index

tumor-associated macrophage

T cell receptors

transforming growth factor beta

Toll-like receptors

tumor microenvironment

tumor necrosis factor-alpha

regulatory T cells

upper respiratory tract infections

maximal oxygen consumption rate

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