Cancer-Associated Fibroblasts Functions as Multifunctional Architects of the Tumor Stroma and Represent Emerging Therapeutic Vulnerabilities.

Cancer-associated fibroblasts (CAFs) are the predominant stromal components within the tumor microenvironment (TME), playing multifaceted roles in cancer progression through dynamic interactions with neoplastic and immune cells. Emerging evidence has revealed remarkable heterogeneity and plasticity of CAFs, which originate from diverse cellular precursors. This cellular diversity, coupled with dynamic epigenetic reprogramming and bidirectional cross-talk with tumor cells, generates distinct CAF subsets with specialized functional outputs. Here, we systematically review the current understanding of CAF biology, encompassing their cellular origins, molecular heterogeneity, and the complex signaling networks. We discuss the functional of CAFs, detailing their protumorigenic roles in extracellular matrix (ECM) remodeling, immunosuppressive niche formation, metabolic reprogramming, angiogenesis, therapy resistance, and maintenance of cancer stem cell properties, while also highlighting emerging evidence for tumor-restrictive CAF subsets. We critically evaluate therapeutic strategies targeting CAFs, including direct depletion approaches, ECM modulation, disruption of CAF-tumor cross-talk, and emphasis on clinical trials and associated challenges. Finally, we outline future directions leveraging single-cell multiomics, patient-derived models and combinatorial regimens to translate current understanding of CAF biology into effective stroma-targeted therapies. This comprehensive framework not only positions CAFs as central architects of tumor ecosystems but also reveals actionable therapeutic vulnerabilities at the intersection of stromal biology and precision oncology.