CD8+ T cells are the core effector cells of antitumor immunity. However, their functionality is vulnerable to metabolic stress within the tumor microenvironment (TME), and they experience significant inhibition from immunosuppressive signals, such as PD-1/PD-L1 and myeloid-derived suppressor cells (MDSC). This review explores how exercise enhances CD8+ T-cell antitumor efficacy through multidimensional synergistic mechanisms. At the molecular level, exercise stimulates the IL-15/IL-15Rα signaling pathway and triggers the release of myokines such as IL-6 and IL-7. These changes considerably boost CD8+ T-cell proliferation, viability, and granzyme B-dependent tumoricidal activity. Concurrently, exercise improves metabolic adaptation and sustains antitumor effects via metabolic reprogramming, which involves enhancing mitochondrial oxidative phosphorylation and increasing lactate-mediated stemness. Moreover, exercise optimizes TME vascular structure, downregulates PD-L1 expression, reduces MDSC proportion, and transforms the immunosuppressive environment, thus facilitating CD8+ T-cell infiltration and long-term function. Preclinical studies have verified that exercise works in tandem with immune checkpoint inhibitors, like anti-PD-1, to improve T-cell homing and counteract the depletion phenotype through the CXCR3-CXCL9/10 axis. Despite the positive progress, the mechanisms of exercise intensity, individual heterogeneity, and dynamic regulation of TME need to be explored in depth. Future studies need to combine multi-omics and dynamic immune monitoring to develop personalized exercise interventions based on CD8+ T-cell profiles. Exercise provides a low-cost, low-risk adjuvant strategy for cancer immunotherapy by targeting CD8+ T-cell function and TME remodeling, and its clinical translational potential needs large-scale validation. Graphical abstract Key mechanisms of exercise in boosting CD8+ T-cell antitumor responses. Exercise combats CD8+ T-cell dysfunction within the TME by (1) direct activation: releasing adrenaline/norepinephrine and myokines (IL-6/7/15) to promote proliferation and survival; (2) metabolic reprogramming: enhancing mitochondrial metabolism and leveraging lactate to sustain stemness; (3) TME remodeling: downregulating PD-L1, reducing MDSCs, and enhancing chemokine (CXCR3/CXCL9/10) signaling to improve T-cell infiltration; and (4) therapeutic synergy: potentiating the efficacy of immune checkpoint inhibitors.

Exercise and CD8⁺ T cells: mechanisms of immune modulation in antitumor responses

期刊论文
发表日期：

2026年3月21日

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Li Liu,
Zhihao Deng,
Ruiying Fang,
Mi Zou,
Junlin Ren,
Yuan Gao,
Jie Peng,
Liang Hao

摘要

CD8⁺ T cells are the core effector cells of antitumor immunity. However, their functionality is vulnerable to metabolic stress within the tumor microenvironment (TME), and they experience significant inhibition from immunosuppressive signals, such as PD-1/PD-L1 and myeloid-derived suppressor cells (MDSC). This review explores how exercise enhances CD8⁺ T-cell antitumor efficacy through multidimensional synergistic mechanisms. At the molecular level, exercise stimulates the IL-15/IL-15Rα signaling pathway and triggers the release of myokines such as IL-6 and IL-7. These changes considerably boost CD8⁺ T-cell proliferation, viability, and granzyme B-dependent tumoricidal activity. Concurrently, exercise improves metabolic adaptation and sustains antitumor effects via metabolic reprogramming, which involves enhancing mitochondrial oxidative phosphorylation and increasing lactate-mediated stemness. Moreover, exercise optimizes TME vascular structure, downregulates PD-L1 expression, reduces MDSC proportion, and transforms the immunosuppressive environment, thus facilitating CD8⁺ T-cell infiltration and long-term function. Preclinical studies have verified that exercise works in tandem with immune checkpoint inhibitors, like anti-PD-1, to improve T-cell homing and counteract the depletion phenotype through the CXCR3-CXCL9/10 axis. Despite the positive progress, the mechanisms of exercise intensity, individual heterogeneity, and dynamic regulation of TME need to be explored in depth. Future studies need to combine multi-omics and dynamic immune monitoring to develop personalized exercise interventions based on CD8⁺ T-cell profiles. Exercise provides a low-cost, low-risk adjuvant strategy for cancer immunotherapy by targeting CD8⁺ T-cell function and TME remodeling, and its clinical translational potential needs large-scale validation.

Graphical abstract

Key mechanisms of exercise in boosting CD8⁺ T-cell antitumor responses. Exercise combats CD8⁺ T-cell dysfunction within the TME by (1) direct activation: releasing adrenaline/norepinephrine and myokines (IL-6/7/15) to promote proliferation and survival; (2) metabolic reprogramming: enhancing mitochondrial metabolism and leveraging lactate to sustain stemness; (3) TME remodeling: downregulating PD-L1, reducing MDSCs, and enhancing chemokine (CXCR3/CXCL9/10) signaling to improve T-cell infiltration; and (4) therapeutic synergy: potentiating the efficacy of immune checkpoint inhibitors.

Exercise and CD8+ T cells: mechanisms of immune modulation in antitumor responses

摘要

Exercise and CD8⁺ T cells: mechanisms of immune modulation in antitumor responses