Heterogeneity of Cancer‐Associated Fibroblasts and Precision Targeting Strategies for Cancer Therapy

ABSTRACT Immune checkpoint blockade (ICB) has transformed cancer therapy, but its effect is often limited by immunosuppression and resistance mechanisms within the tumor microenvironment (TME). Cancer‐associated fibroblasts (CAFs) represent a major stromal component of the TME. They exhibit substantial heterogeneity, dynamic plasticity, diverse cellular origins, and context‐dependent activation states, which critically determine the safety and efficacy of CAF‐targeted therapies. CAFs contribute to tumor immune evasion by remodeling the extracellular matrix, altering tissue mechanics and establishing structural barriers. In addition, CAFs release cytokines, chemokines, and exosomes to impair T‐cell trafficking and function. They also interact with immune and myeloid cells, further reducing the efficacy of ICB. Therefore, CAF‐targeted therapies are shifting from the strategy of extensive clearance to a more elaborate framework, which focuses on specific CAF subpopulations and their regulatory pathways, and combines specific strategies for subpopulations, functional reprogramming, and methods based on advanced delivery systems and diagnostic tools. Integrating spatial omics, single‐cell technologies, and 3D culture systems can help us better understand the different states of CAFs and how they are distributed in space. This enables the identification of targetable CAF states, informs reprogramming strategies, supports rational combination design, and facilitates biomarker discovery. This review emphasizes the heterogeneity and plasticity of CAFs in tumor immunosuppression, and advocates a conceptual shift from static cellular identity to a dynamic state–niche–function framework.