1.3. Cancer-associated fibroblasts (CAFs):
Non-malignant stromal cells in the tumor microenvironment are crucial for drug resistance and tumor progression [112]. Stromal cells are polarized by their interaction with tumor cells, and through education of tumor cells, they secrete diverse molecules, resulting in pharmacokinetics regulation, immunosuppression, and metabolic regulation, subsequently, they reduce therapeutic outcomes [112]. The most common type of stromal cells are CAFs. CAFs by involvement in ECM remodeling and metabolic reprogramming, as well as by secretion of diverse factors such as cytokines (IL-6, IL-8, IL-10, etc.), growth factors (hepatocyte growth factor, stromal cell-derived factor, fibroblast growth factor, transforming growth factor), various chemokines, metabolites, and exosomes (contain lncRNAs, miRNAs and mitochondrial DNA (mtDNA)) which activate multiple signaling cascades, cause drug resistance, and ultimately tumor recurrence [111, 112, 120].