Therapy-induced senescent cancer-associated fibroblasts in cervical cancer: Mechanisms of treatment resistance and therapeutic opportunities

Abstract

Cervical cancer remains a major global health burden, and concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced disease. However, a substantial proportion of patients develop residual disease, recurrence, or progression after treatment. In addition to tumor cell–intrinsic mechanisms, accumulating evidence indicates that therapeutic resistance is strongly influenced by the tumor microenvironment (TME), particularly through the functional remodeling of cancer-associated fibroblasts (CAFs). Therapy-induced senescence has recently emerged as a potential mechanism linking treatment-related stromal injury to persistent microenvironmental adaptation. CAFs in cervical cancer exhibit substantial heterogeneity and plasticity, complicating the identification of therapy-induced senescent states. Radiotherapy and CCRT may induce senescence-like phenotypes in a subset of CAFs, generating putative senescent cancer-associated fibroblasts (sCAFs) characterized by persistent viability, reduced proliferative capacity, and sustained metabolic and secretory activity. These cells may remodel the post-treatment microenvironment through senescence-associated secretory phenotype (SASP) signaling, extracellular matrix reorganization, immune modulation, and metabolic crosstalk, thereby potentially supporting the survival and adaptation of residual tumor cells. This review summarizes the biological origins and functional states of CAFs, discusses current criteria for identifying therapy-induced sCAFs, and evaluates the mechanisms by which they may contribute to treatment resistance. We also distinguish direct cervical cancer-specific evidence from cross-tumor mechanistic extrapolation and discuss emerging therapeutic strategies, including senolytics, senomorphics, stromal reprogramming, metabolic intervention, and targeted drug delivery. Therapy-induced sCAF offers a plausible framework for understanding post-CCRT microenvironmental remodeling and treatment resistance in cervical cancer. Current evidence supports viewing putative sCAFs as heterogeneous, stress-adapted CAF states rather than a discrete lineage, highlighting the need for composite biological and spatial criteria for their identification. Establishing their clinical relevance, temporal evolution, and resistance-associated subpopulations will be essential for developing biomarker-guided stromal interventions that can be safely integrated with CCRT.