Exercise enhances cancer immunotherapy by reshaping systemic T cell homeostasis

Although immune checkpoint inhibitors have revolutionized cancer treatment, therapeutic resistance and heterogeneous patient responses remain major clinical challenges. Current paradigms predominantly focus on amplifying effector T cells (Teffs); however, this approach frequently encounters structural bottlenecks imposed by a tumor-locked, suppressive immune homeostasis. Central to this aberrant equilibrium are regulatory T cells (Tregs), which persistently elevate immune activation thresholds and restrict durable antitumor responses. In this review, we propose a paradigm shift toward reshaping baseline T cell homeostasis, highlighting exercise as a potent, systemic physiological intervention. Regular exercise systematically counteracts tumor-induced homeostatic locking by reprogramming immune metabolism, attenuating chronic inflammation, and improving tissue perfusion. Rather than indiscriminately depleting Tregs, exercise dynamically recalibrates the Teff/Treg balance, lowering activation thresholds while preserving systemic immune tolerance. Furthermore, we propose that structured physical activity may support a form of “homeostatic memory,” with potential implications for the durability of immunotherapy responses. Integrating exercise into oncological care offers a translational, host-centered strategy to optimize the immune background, thereby unlocking the full clinical potential of cancer immunotherapy.