Myokine-mediated mechanisms of immune checkpoint inhibitors-associated colorectal injury and repair in rectal cancer.

Rectal cancer exhibits prominent anatomical and molecular heterogeneity, shaping a tumor microenvironment that determines responsiveness to immune checkpoint inhibitors (ICIs). Though ICIs exert robust anti-tumor effects on dMMR/MSI-H rectal tumors, overactivated immunity causes ICI-associated colorectal injury (ICI-CRI) characterized by diarrhea, mucosal ulceration and even perforation. Its pathological mechanisms cover CD8+ T cell-mediated epithelial cytotoxicity, inflammatory cytokine cascades, gut dysbiosis-induced endotoxin translocation, microvascular hypoperfusion, lactic acid accumulation and extracellular matrix fibrosis. Skeletal muscle-secreted myokines (IL-6, IL-15, irisin) form a critical gut-muscle regulatory axis: IL-15 and irisin protect intestinal mucosa by restraining immunosuppressive cells, while excess muscle-derived IL-6 amplifies intestinal inflammation.

Multimodal imaging combined with radiomics and artificial intelligence realizes quantitative monitoring of mucosal, vascular and fibrotic lesions. Stratified management schemes including stepwise immunosuppression, microbiota reconstruction, metabolic support and muscle-targeted exercise/nutrition can interrupt the vicious loop linking sarcopenia and intestinal damage. This review systematically illustrates the myokine-centered regulatory network, providing theoretical references to maximize ICI efficacy while reducing gastrointestinal toxicity for personalized rectal cancer immunotherapy.