Exercise as an epigenetic modifier of cancer-associated inflammation: Unraveling the DNA methylation, histone modification, and non-coding RNA circuitry.

Chronic inflammation is a hallmark of cancer, driving initiation, progression, and metastasis through sustained pro-inflammatory signaling and immune microenvironment remodeling. Physical exercise reduces systemic low-grade inflammation and improves cancer outcomes, yet the molecular conduits linking transient exercise stress to durable anti-inflammatory effects remain poorly defined. Epigenetic mechanisms-DNA methylation, histone modifications, and non-coding RNAs-translate environmental stimuli into stable gene expression changes. In this review, we dissect the tripartite interplay between physical exercise, epigenetic regulation, and cancer-associated inflammation. We first outline how chronic inflammatory signaling aberrantly reprograms the cancer epigenome, silencing tumor-suppressor and pro-resolution genes via promoter hypermethylation and repressive histone marks, while activating oncogenic and pro-inflammatory mediators through permissive chromatin states. We then synthesize evidence that structured exercise counteracts this corruption by modulating DNA methyltransferases, TET dioxygenases, and histone deacetylases, thereby reversing pathological methylation and acetylation patterns at inflammatory loci. We further examine how exercise-induced circulating microRNAs and exosomal cargo propagate these epigenetic signals systemically to distant tumor niches. A mechanistic model is proposed wherein exercise-dependent epigenetic reprogramming attenuates NF-κB-driven inflammatory circuits and restores immune surveillance. Finally, we identify critical knowledge gaps-tissue-specificity, dose-response relationships, and durability of exercise-induced epigenetic modifications-that must be addressed to translate the exercise-epigenetics-inflammation axis into personalized cancer prevention and therapy.