Cancer-Associated Fibroblasts evolution in the tumor microenvironment: orchestrating immune evasion and therapeutic resistance

Cancer biology research increasingly recognizes the tumor microenvironment (TME) as a vital determinant of disease progression and therapeutic outcomes. Among the diverse cellular components of the TME, Cancer-Associated Fibroblasts (CAFs) have emerged as key modulators of tumor behavior due to their remarkable plasticity and functional heterogeneity. Recent findings have underscored that CAFs are not passive bystanders but dynamic participants in cancer evolution, continuously adapting under therapeutic pressure. Their evolution into distinct subpopulations—such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs)—illustrates the complexity of their roles in tumor survival and resistance. Despite growing recognition of their importance, the precise molecular and cellular mechanisms orchestrating CAF evolution and their contributions to treatment failure remain incompletely understood.Recent studies have demonstrated that CAFs actively remodel the extracellular matrix (ECM) and secrete immunoregulatory mediators including TGF-β, IL-6, and CXCL12, which establish a protective niche for tumor cells. These factors promote immune evasion by impairing cytotoxic T cell and NK cell activity while recruiting immunosuppressive Tregs and myeloid-derived suppressor cells. Moreover, ECM remodeling by CAFs creates physical barriers that hinder the penetration of drugs and immune cells, further exacerbating resistance to therapy. Cutting-edge single-cell and spatial transcriptomic analyses are beginning to map the lineage trajectories and dynamic phenotypic shifts of CAFs under various therapeutic regimens. Still, a comprehensive understanding of how these mechanisms interconnect to sustain tumor resilience is lacking, underscoring the necessity of systematic investigation into CAF evolution within the TME.This Research Topic aims to advance our comprehension of how Cancer-Associated Fibroblasts evolve under therapeutic pressures and how these adaptive transformations contribute to immune evasion and drug resistance. By collating multidisciplinary insights from molecular biology, immunology, and systems oncology, this collection seeks to identify the signaling, genetic, and epigenetic networks driving CAF reprogramming. It also aims to highlight innovative strategies for therapeutically targeting CAF plasticity—either to prevent pro-tumorigenic remodeling of the TME or to reprogram CAFs toward tumor-suppressive phenotypes. Key questions include: What are the evolutionary triggers of CAF heterogeneity in treated tumors? How does the CAF secretome remodel immune and stromal interactions post-therapy? And can CAF-derived biomarkers predict and overcome treatment resistance?To gather further insights into the dynamic evolution and functional plasticity of CAFs, this Research Topic welcomes Original Research and Reviews addressing, but not limited to, the following themes:• Molecular mechanisms (genetic, epigenetic, and metabolic) driving CAF evolution and heterogeneity under therapy.• Functional roles of distinct CAF subsets (iCAFs, myCAFs, apCAFs) in immunotherapy, chemotherapy, and targeted therapy resistance.• Crosstalk between evolving CAF subpopulations and immune cells, including Tregs, MDSCs, macrophages, and CD8+ T cells.• CAF-mediated ECM remodeling as a barrier to immune infiltration and drug delivery.• The CAF secretome (cytokines, chemokines, extracellular vesicles) in sustaining immunosuppression after therapy.• Novel approaches to target or reprogram pro-tumorigenic CAFs to restore treatment sensitivity.• Identification and validation of CAF-related biomarkers predicting treatment response and resistance.• Advanced experimental models (e.g., organoids, patient-derived xenografts, single-cell multiomics) for studying CAF evolution. Topic editors: Jun Jiang, Qiong Lu, Hongtao Song Source: https://www.frontiersin.org/research-topics/80692/cancer-associated-fibroblasts-evolution-in-the-tumor-microenvironment-orchestrating-immune-evasion-and-therapeutic-resistance