Radiation-Induced Alterations in Cancer-Associated Fibroblasts: Drivers of Tumor Radioresistance and Therapeutic Targets.

Abstract

Radiotherapy serves as a cornerstone of cancer treatment, but its efficacy is often compromised by radioresistance, a process in which cancer-associated fibroblasts (CAFs) play a critical role. Following irradiation, CAFs exhibit inherent radioresistance, not only surviving at higher doses but also undergoing profound functional reprogramming, including senescence, acquisition of a senescence-associated secretory phenotype (SASP), and myofibroblast activation. Importantly, CAFs employ multiple interconnected mechanisms to collectively drive radioresistance: sustained immunosuppression, pro-resistance paracrine signaling, exosome-mediated communication, and stromal remodeling. These reprogrammed CAFs create a microenvironment that paradoxically supports tumor recurrence and limits therapeutic efficacy. Intervention strategies targeting CAFs-including neutralizing soluble factors, blocking key signaling nodes, targeted therapies against fibroblast activation proteins, or disrupting exosome-mediated communication-have shown promise in preclinical studies. A deeper understanding of the complex interactions between radiotherapy and CAFs may ultimately drive a shift in therapeutic strategy from targeting tumor cells alone to leveraging the entire microenvironment to achieve durable antitumor effects.