Cancer-Associated Fibroblasts in Solid Tumors and Sarcomas: Heterogeneity, Function, and Therapeutic Implications

Cancer-associated fibroblasts (CAFs) are crucial regulators of the tumor microenvironment (TME), promoting cancer progression, immune suppression, and therapy resistance. Single-cell transcriptomics has identified at least five distinct CAF subtypes: myofibroblastic (myCAFs), inflammatory (iCAFs), antigen-presenting (apCAFs), metabolic (meCAFs), and vascular/developmental (vCAFs/dCAFs), each with unique localization, signaling, and functions. While CAFs are well studied in epithelial cancers, their roles in sarcomas are less understood despite the shared mesenchymal origin of tumor and stromal cells. This overlap blurs the line between malignant and non-malignant fibroblasts, raising fundamental questions about the identity of CAFs in mesenchymal tumors. In this narrative review, we explore the heterogeneity and plasticity of CAFs across solid tumors, focusing on their role in immune evasion, epithelial-to-mesenchymal transition (EMT), and resistance to chemotherapy, targeted therapy, and immunotherapy. We highlight emerging evidence on CAF-like cells in sarcomas and their contribution to tumor invasion, immune exclusion, and metastatic niche formation. We also assess new strategies to target or reprogram CAFs and suggest that CAF profiling may serve as a potential biomarker for patient stratification. Understanding CAF biology across various tumor types, including those with dense stroma and immunologically cold sarcomas, is crucial for developing more effective, personalized cancer treatments.