Mechanosensitive epitranscriptomics in cancer: linking tumor mechanics, RNA modification, and immune escape

Abstract

Solid tumors are mechanically abnormal ecosystems in which extracellular matrix stiffening, compressive stress, interstitial pressure, and aberrant fluid flow reshape cancer, stromal, and immune cell behavior. In parallel, the cancer epitranscriptome has emerged as a dynamic regulatory layer in which RNA modifications, including m 6 A, m 5 C, m 7 G, pseudouridine, and A-to-I editing, control RNA stability, translation, splicing, localization, and immune recognition. This review proposes mechanosensitive epitranscriptomics as an integrative framework linking these two fields. We discuss how canonical mechanotransduction pathways, including integrin–FAK signaling, YAP/TAZ activation, PIEZO1-mediated calcium influx, cytoskeletal remodeling, and nuclear deformation, may converge on RNA writers, erasers, readers, editing enzymes, RNA-binding proteins, noncoding RNAs, and ribonucleoprotein condensates. Particular emphasis is placed on the tumor–immune interface, where mechanical stress and RNA modifications jointly influence antigen presentation, interferon signaling, checkpoint expression, metabolic adaptation, T-cell and NK-cell function, myeloid polarization, and immune exclusion. At present, only two studies in the evidence set reviewed here meet the Tier-1 definition in cancer-relevant systems: the PDAC stiffness–METTL14/IGF2BP3–YAP1 study and the macrophage stiffness–FTO–Socs1 study, whereas most broader cancer-specific links remain Tier-3 hypotheses or mechanically confounded associations. We highlight evidence gaps and propose testable models to distinguish direct mechanoregulation from secondary effects of hypoxia, inflammation, and metabolism. Finally, we outline experimental and translational strategies for mapping mechanical niches, defining causal RNA-modification circuits, and developing composite biomarkers that integrate tumor mechanics, epitranscriptomic states, and immunotherapy response.