Modeling CAF-tumor interactions to overcome therapy resistance

Cancer-associated fibroblasts (CAFs) represent an interesting component of the tumor microenvironment, playing a crucial role in cancer progression, metastasis, and treatment resistance. This review provides a comprehensive overview of identified subtypes across various cancer types, highlighting their inter-tumor heterogeneity, plasticity, and function of the different CAF phenotypes. With a focus on renal cell carcinoma, we reviewed the correlations between CAF markers, disease progression, and treatment outcomes. This approach underlined the existence of CAF-induced drug resistance and therapeutic strategies that can be utilized to overcome this extrinsic resistance. A major focus of this review is the role of CAFs in inducing drug resistance, a phenomenon observed in both in vivo and in vitro cancer models. We discuss the integration of CAFs in several in vitro co-culture systems cultivated in two- and three-dimensional models, as well as their contributions to deciphering CAF-tumor crosstalk. These platforms better recapitulate the tumor microenvironment, reflecting CAF-induced therapeutic resistance. Ultimately, this review underlines the crucial role of CAF-incorporated co-culture systems in advancing drug development, especially in the context of tissue- and subtype-specific CAF targeting.