Exercise-induced myokines show functional duality with tumor-suppressive or tumor-promoting effects depending on microenvironmental context

Cancer remains a major threat to human health. Exercise has been shown to reduce cancer risk, inhibit tumor progression, and improve patient prognosis and quality of life; however, its precise molecular underpinnings are not yet fully understood. To synthesize current evidence and identify critical knowledge gaps, this review focuses on exercise-induced myokines secreted by skeletal muscle and examines their potential direct and indirect roles in tumorigenesis and malignant progression. We systematically reviewed the molecular mechanisms by which several key exercise-responsive myokines exert tumor-suppressive effects, including interleukin-6 (IL-6), Secreted Protein Acidic and Rich in Cysteine (SPARC), irisin, and other prominent myokines. Significant progress has been made in elucidating the antitumor mechanisms of major myokines. Nevertheless, their intracellular signaling pathways remain incompletely defined. The majority of existing studies rely on in vitro cell models and lack validation in physiologically relevant in vivo settings or clinical contexts. Notably, several myokines exhibit functional duality, capable of exerting either tumor-suppressive or tumor-promoting effects depending on the specific microenvironmental context. Future research must urgently delineate the interaction networks of myokines with their upstream regulators and downstream effectors. It is essential to validate their true in vivo mechanisms using standardized animal models and well-characterized clinical samples. Furthermore, systematic evaluation of their pharmacokinetics, delivery strategies, and potential off-target effects is required to advance the clinical translation of myokine-based therapeutic interventions.