Cancer‐Associated Fibroblasts: Origin, Classification, Tumorigenicity, and Targeting for Cancer Therapy

ABSTRACT Cancer‐associated fibroblasts (CAFs) are pivotal stromal components that shape the tumor microenvironment through their remarkable heterogeneity and dynamic functions. This review comprehensively examines the biology of CAFs, starting with their diverse cellular origins and induction mechanisms via key signaling pathways. We highlight the spatial‐temporal heterogeneity of CAF subsets and propose an updated classification system that encompasses eight functionally distinct subtypes based on recent single‐cell transcriptomic studies. The tumor‐promoting roles of CAFs are explored in depth, including their contributions to tumor behavior through novel mechanisms such as neutrophil extracellular traps formation, and multidrug resistance via metabolic reprogramming. A major focus is placed on CAF‐mediated immunotherapy resistance through immune checkpoint regulation, recruitment of immunosuppressive cells, and metabolite secretion. This review also highlights key technologies that are advancing CAF research, including patient‐derived 3D models, artificial intelligence‐enhanced spatial multiomics, clustered regularly interspaced short palindromic repeats (CRISPR)‐engineered mouse systems, and machine learning approaches for analyzing CAF heterogeneity and function. Finally, we evaluate therapeutic strategies targeting CAF activation, secreted factors, and immune crosstalk, while critically analyzing ongoing clinical trials. Overall, this review not only clarifies the biology of CAFs but also provides a translational framework for developing next‐generation stromal‐targeted therapies to overcome treatment resistance in cancer.