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Figure 1. Mechanisms of resistance to chemotherapy. Tumor cell-intrinsic mechanisms may involve: dysregulated expression of drug transporters (SLC family members or ATP7B) and enzymes involved in drug metabolism (CYP family members), imbalanced expression of anti-/pro-apoptotic molecules (BAX mutation/loss or increased BCL2 expression), or dysregulation of DNA repair mechanisms and checkpoints (TP53 mutation/loss, MMR proteins mutation, diminished expression of BER proteins, or increased ERCC6 expression). External signals acting on the tumor cells to trigger resistance may derive from the cells populating the tumoral niche such as the CAFs releasing TGFB, osteopontin and exosomes containing specific lncRNAs and miRs. In addition, inflammatory and immunitary cells of the niche release a number of interleukins, growth factors, pro-angiogenic factors. Also, specific components of the microbiota can contribute to the resistance to chemotherapy by directly inactivating the drug (Gammaproteobacterial or M. hyorhinis) or by engaging the TLR4/MyD88 system to transduce pro-survival and autophagic signals. SLC: Solute carrier; MMR: mismatch-repair system; CAFs: cancer-associated fibroblast.