Skeletal muscle dysfunction induced by cancer immunotherapy: mechanistics insights and surgical implications

Cancer immunotherapy has revolutionized cancer treatment, yet its effects extend far beyond tumor eradication. Accumulating evidence indicates that immunotherapy-associated skeletal muscle dysfunction represents a complex, cross-organ pathological process driven by dynamic crosstalk between the tumor microenvironment and peripheral tissues. Rather than an isolated adverse event, muscle injury emerges from integrated mechanisms including inflammatory cytokine spillover, aberrant immune cell infiltration, metabolic reprogramming, vascular dysfunction, and impaired regenerative signaling. Central to this process is the sustained activation of the NF-κB and JAK/STAT3 axes, which links systemic immune activation to ubiquitin-proteasome-mediated proteolysis, mitochondrial dysfunction, and suppression of anabolic pathways. Meanwhile, metabolic coupling between tumor glycolysis and skeletal muscle energetics establishes a bidirectional feedback loop that exacerbates catabolism and compromises antitumor immunity. Clinically, baseline sarcopenia and therapy-induced myotoxicity reciprocally impair immunotherapeutic efficacy, forming a self-reinforcing cycle that limits treatment continuity and long-term survival. Advances in multimodal imaging, including PET/CT, shear wave elastography, and dynamic contrast-enhanced MRI, combined with artificial intelligence-driven quantitative analysis, provide a noninvasive framework to decode metabolic, mechanical, and vascular signatures of muscle vulnerability. Emerging interventions targeting inflammatory signaling, metabolic imbalance, vascular dysregulation, and regenerative pathways offer promising strategies to dissociate antitumor efficacy from systemic toxicity. Future research should prioritize longitudinal, multi-omics-integrated, and imaging-guided approaches to clarify causal hierarchies and enable precision risk stratification. Bridging mechanistic insight with perioperative and translational strategies will be essential to achieving comprehensive cancer care in the immunotherapy era.