A review of soluble mediator and cytokine networks linking combination immunotherapy, tumor microenvironment remodeling and skeletal muscle dysfunction
TL;DR
An integrated mechanistic and translational framework is established to advance holistic oncologic care that reconciles robust anti-tumor immunity with sustained skeletal muscle integrity that reconciles robust anti-tumor immunity with sustained skeletal muscle integrity.
Abstract
Combinatorial immunotherapies have revolutionized the clinical management of advanced malignancies, yet their prominent anti-tumor efficacy is frequently compromised by treatment-induced skeletal muscle dysfunction governed by reciprocal signaling circuitry bridging the tumor microenvironment (TME) and peripheral muscle compartments. This review systematically delineates conserved soluble mediator and cytokine networks underlying therapy-triggered myotoxicity across five core combinatorial regimens, chemoimmunotherapy, targeted immunotherapy, gene therapy, tumor vaccines, and CAR-T cell therapy, alongside modality-specific toxic signaling axes. Cancer-associated fibroblast-derived TGF-β, glycolysis-originated lactate, and IL-6/TNF-α-centered inflammatory cascades converge to activate the myostatin/FoxO3 transcriptional program and ubiquitin-proteasome proteolysis, disrupting muscle anabolic-catabolic homeostasis. Type II fast-twitch glycolytic fibers and muscle satellite cells display disproportionate susceptibility to inflammatory and metabolic damage, whereas clinical confounders including corticosteroid exposure, chronological age, and sex hormones stratify interpatient vulnerability to muscle wasting. Conventional and emerging skeletal muscle biomechanical assessment modalities are critically benchmarked, with electrical impedance myography highlighted as a high-sensitivity platform for subclinical tissue remodeling detection, and tiered multimodal monitoring pipelines are formulated for prospective immunotherapy clinical trials. Translational muscle-protective interventions covering structured resistance training, personalized nutritional supplementation, and anti-cachexia pharmacotherapy are comprehensively consolidated. Collectively, this review establishes an integrated mechanistic and translational framework to advance holistic oncologic care that reconciles robust anti-tumor immunity with sustained skeletal muscle integrity.