Exercise-modulated IL-6 in cancer cachexia: molecular mechanisms and therapeutic potential

BACKGROUND: Cancer cachexia is a multifactorial metabolic syndrome marked by progressive skeletal muscle wasting, systemic inflammation, reduced quality of life, and poor clinical outcomes. Interleukin-6 (IL-6) is a central mediator in cachexia pathophysiology, driving inflammatory signaling, catabolic metabolism, and muscle atrophy. However, IL-6 also rises transiently during exercise, where it exerts beneficial metabolic and anti-inflammatory effects, highlighting the context-dependent nature of IL-6 signaling. MAIN BODY: This review summarizes current knowledge on the regulation and function of IL-6 in cancer cachexia and examines how exercise training modulates IL-6 production and downstream signaling pathways. We focus on the mechanistic differences between chronic, tumor-derived IL-6 and acute, exercise-induced IL-6, particularly their divergent effects on the JAK/STAT3, NF-κB, and AMPK cascades. In addition, we review preclinical and clinical evidence demonstrating that exercise can attenuate cachexia by reprogramming inflammatory responses, preserving skeletal muscle mass, and improving metabolic homeostasis. CONCLUSIONS: Accumulating evidence indicates that structured exercise interventions may represent a promising non-pharmacological adjunct to counteract IL-6-driven cancer cachexia and improve patient outcomes. Future research should aim to optimize exercise prescriptions and explore potential synergistic effects between exercise and IL-6-targeted therapies to enhance therapeutic efficacy in cachectic cancer patients.