Regular exercise is associated with improved outcomes for many patients with cancer, yet those with advanced disease may be unable to participate in exercise-based interventions. In a new Perspective published in EXO – Beyond the Cell, Dr. Emma S. Kurz (Massachusetts General Hospital and Memorial Sloan Kettering Cancer Center) and Prof. Dafna Bar-Sagi (NYU Langone Hospital) argue that this challenge should reshape-not limit-the future of exercise oncology.

Rather than viewing preclinical exercise research mainly as evidence supporting exercise prescriptions, the authors propose a broader framework: exercise oncology should serve as a discovery engine for identifying anti-tumor mechanisms that can be translated into therapies independent of exercise itself. By uncovering the molecular pathways activated during physical activity, researchers may be able to develop new pharmacological strategies capable of benefiting patients who cannot exercise because of frailty, cachexia, treatment-related toxicities, or other co-morbidities.

To illustrate this concept, the authors highlight three emerging areas where mechanistic insights from exercise research are already informing translational opportunities.

The first involves exercise-induced metabolic remodeling. Studies discussed in the Perspective show that exercise-associated changes in circulating metabolites, particularly lactate, can reprogram CD8⁺ T cells toward a more active anti-tumor state. Experimental evidence further suggests that administration of lactate alone can reproduce some of these immune effects without requiring exercise, raising the possibility that exercise-induced circulating factors, or "exerkines," could become future therapeutic candidates.

The authors next examine the gut microbiome, where exercise has been shown to reshape microbial metabolism and alter production of metabolites such as formate. Recent preclinical findings suggest these changes can enhance anti-tumor immunity and improve responses to immune checkpoint blockade. Such discoveries point toward future microbiome-based strategies-including fecal microbiota transplantation or targeted microbial interventions-that may capture selected benefits of exercise for patients unable to engage in physical activity.

A third example focuses on immune signaling and the myokine IL-15. Exercise stimulates release of cytokines that influence immune surveillance, and preclinical studies indicate that activation of the IL-15 pathway can reproduce important anti-tumor immune responses in pancreatic cancer models even in the absence of exercise. These findings further support the idea that exercise biology can reveal actionable therapeutic targets rather than simply validate exercise interventions.

The authors emphasize that these concepts are not intended to replace exercise in cancer care. Exercise produces complex systemic effects that cannot be fully replicated by targeting a single pathway. Instead, they propose that mechanistic discoveries from exercise oncology should complement clinical exercise programs, expanding therapeutic possibilities for patients who are unable to participate while also informing future precision cancer therapies.

By reframing exercise oncology as a platform for biological discovery, the authors present a new perspective on how the field can move beyond the treadmill-transforming physiological insights into innovative therapeutic opportunities that may ultimately extend the anti-cancer benefits of exercise to patients who need them most.

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