Heterotypic signaling of cancer-associated fibroblasts in shaping the cancer cell drug resistance.

The context-dependent reciprocal interaction between the cancer cells and surrounding fibroblasts is imperative for regulating malignant potential, metabolic reprogramming, immunosuppression, and ECM deposition. However, recent evidence also suggests that cancer-associated fibroblasts induce chemoresistance in cancer cells to various anticancer regimens. Because of the protumorigenic function of cancer-associated fibroblasts, these stromal cell types have emerged as fascinating therapeutic targets for cancer. However, this notion was recently challenged by studies that targeted cancer-associated fibroblasts and highlighted the underlying heterogeneity by identifying a subset of these cells with tumor-restricting functions. Hence, it is imperative to understand the heterogeneity and heterotypic signaling of cancer-associated fibroblasts to target tumor-promoting signaling processes by sparing tumor-restricting ones. In this review, we discuss the heterogeneity and heterotypic signaling of cancer-associated fibroblasts in shaping drug resistance and also list the cancer-associated fibroblast-targeting therapeutics.