Badran Omar, Cohen Idan, Bar-Sela Gil
Department of Oncology, Emek Medical Center, Afula 1834111, Israel.
Technion Integrated Cancer Center, Faculty of Medicine, Technion, Haifa 3525422, Israel.
Cells. 2025 Sep 7;14(17):1398. doi: 10.3390/cells14171398.
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.
癌症相关成纤维细胞（CAFs）是肿瘤微环境（TME）的关键调节因子，可促进癌症进展、免疫抑制和治疗抵抗。单细胞转录组学已鉴定出至少五种不同的CAF亚型：肌成纤维细胞型（myCAFs）、炎症型（iCAFs）、抗原呈递型（apCAFs）、代谢型（meCAFs）和血管/发育型（vCAFs/dCAFs），每种亚型都具有独特的定位、信号传导和功能。虽然CAFs在上皮性癌症中已得到充分研究，但尽管肿瘤细胞和基质细胞具有共同的间充质起源，它们在肉瘤中的作用仍知之甚少。这种重叠模糊了恶性和非恶性成纤维细胞之间的界限，引发了关于间充质肿瘤中CAFs身份的基本问题。在这篇叙述性综述中，我们探讨了实体瘤中CAFs的异质性和可塑性，重点关注它们在免疫逃逸、上皮-间质转化（EMT）以及对化疗、靶向治疗和免疫治疗的抵抗中的作用。我们强调了肉瘤中CAF样细胞的新证据及其对肿瘤侵袭、免疫排斥和转移小生境形成的贡献。我们还评估了靶向或重编程CAFs的新策略，并提出CAF分析可能作为患者分层的潜在生物标志物。了解包括那些具有致密基质和免疫冷性肉瘤在内的各种肿瘤类型中的CAF生物学，对于开发更有效、个性化的癌症治疗至关重要。
