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Figure 2. Fibroblast-mediated signaling in shaping the drug resistance in (A) CAFs promote cancer cells survival by secreting ANXA6, CCL1, CXCL 12, CCL5, MK, etc., and the exosomes containing lncRNA ANRIL, miR-196a, miR-103a-3p, miR-24-3p, microRNA-21, microRNA-148b-3p, LPP, CCAL, etc. Also, CAFs show high levels of netrin1, IL-6, and ATF4, which offer cancer cells gemcitabine resistance. TGF-β1 secreted by cancer cells acts on CAFs to attain 5-fluorouracil (5-FU) and tamoxifen (TAM) resistance. Inhibition of PTEN by CXCL12-CXCR4 binding promotes mTOR signaling and cancer proliferation. MK provides cisplatin resistance by ameliorating the expression of lncRNA-ANRIL; (B) CAFs induce stemness in cancer cells through the activation of STAT3 by IL8, IL6, and FGF and secreting exosomes containing miR-221 and H19 that leads to drug resistance, and STAT3 activation can be inhibited by IL-17A. High levels of α-SMA, Wnt5α, BMP4 and Notch3 in CAFs and low expression of ER in both CAFs and cancer cells are associated with enriching CSCs and drug resistance; (C) CAFs provide different nutrients to cancer cells. CAF-secreted factors rewire the cancer cell metabolism by the activation of autophagy, mTOR, and TIGAR and suppression of oxidative phosphorylation that leads to drug resistance; (D) CAFs promote drug resistance by ECM deposition. Activation of CAFs by TGF-β1 or other factors leads to excessive synthesis of ECM proteins such as laminin-A, collagen, and fibronectin. It also induces various MMPs, which leads to ECM modeling that blocks drug effects.