From CAF heterogeneity to immune modulation and therapeutic targeting: a subtype-based framework

Cancer-associated fibroblasts (CAFs) are the predominant stromal component in solid tumors, contributing to extracellular matrix (ECM) remodeling, immune regulation, and therapy responses. Once considered homogeneous, CAFs are now recognized as a heterogeneous population comprising subtypes with distinct phenotypes and functions. Their plasticity is shaped dynamically by tumor type, context, and stage. Rather than exhaustively cataloguing the expanding number of CAF subpopulations, this review adopts a function-oriented framework centered on three major CAF subtypes: myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs), highlighting subtype-specific markers, spatial organization, differentiation trajectory, and immune functions. This review explores the clinical implications of CAF profiling for prognosis and therapy response and discusses emerging strategies that aim to reprogram CAF subtypes or harness their immune-modulatory potential. It also evaluates current CAF-targeting therapies to identify factors contributing to their therapeutic successes and limitations. By integrating subtype-specific immune functions with clinical evidence, this review aims to inform clinicians considering immunotherapy for patients with solid tumors and provide immunologists with a systematic understanding of CAF heterogeneity and directions for future research. These insights position CAFs not only as barriers to treatment but also as potentially programmable components that offer novel therapeutic opportunities.