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Recent advances in single\u2010cell multiomics and spatial transcriptomics have identified conserved CAF subtypes with distinct molecular signatures, spatial distributions, and context\u2010dependent roles, highlighting their dual capacity to promote immunosuppression or restrain tumor growth. However, therapeutic strategies struggle to reconcile this functional duality, hindering clinical translation. This review systematically categorizes CAF subtypes by origin, biomarkers, and TME\u2010specific functions, focusing on their roles in chemoresistance, maintenance of stemness, and formation of immunosuppressive niches. We evaluate emerging targeting approaches, including selective depletion of tumor\u2010promoting subsets (e.g., fibroblast activation protein+ CAFs), epigenetic reprogramming toward antitumor phenotypes, and inhibition of CXCL12\/CXCR4 or transforming growth factor\u2010beta signaling pathways. Spatial multiomics\u2010driven combinatorial therapies, such as the synergistic use of CAFs and immune checkpoint inhibitors, are highlighted as strategies to overcome microenvironment\u2010driven resistance. By integrating CAF biology with translational advances, this work provides a roadmap for developing subtype\u2010specific biomarkers and precision stromal therapies, directly informing efforts to disrupt tumor\u2010stroma coevolution. Key concepts include spatial transcriptomics, stromal reprogramming, and tumor\u2010stroma coevolution, offering actionable insights for both mechanistic research and clinical innovation.<\/jats:p>","DOI":"10.1002\/mco2.70292","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T07:20:39Z","timestamp":1752218439000},"source":"Crossref","is-referenced-by-count":28,"title":["Cancer\u2010Associated Fibroblasts: Heterogeneity, Cancer Pathogenesis, and Therapeutic Targets"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0998-0291","authenticated-orcid":false,"given":"Yutao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery Peking University People's Hospital  Beijing China"},{"name":"Thoracic Oncology Institute Peking University People's Hospital  Beijing China"},{"name":"Research Unit of Intelligence Diagnosis and Treatment in Early Non\u2010Small Cell Lung Cancer Chinese Academy of 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