miR-155 and the orchestration of cell-death evasion and chemoresistance in cancer: Isoform-specific mechanisms and therapeutic opportunities.

MicroRNA-155 (miR-155) is a crucial miRNA that connects inflammation signaling with epigenetic regulation, impacting programmed cell death (PCD) and influencing chemotherapy resistance. It inhibits apoptosis by targeting pro-apoptotic factors and adjusts autophagy via PDK1/AKT-mTOR activation or downregulating ATG5, helping cells cope with stress. In many solid and hematologic cancers, the predominant pattern involves promoting resistance, mainly through miR-155-5p-driven suppression of pro-apoptotic or checkpoint regulators, involving PI3K/AKT, NF-κB, and STAT3 pathways. Conversely, some studies indicate chemosensitizing or tumor-suppressive roles in specific contexts, such as miR-155-3p/MYD88 signaling in breast cancer, miR-155/XIAP in ovarian cancer, and miR-155/CD47-TNFAIP8 in multiple myeloma. miR-155 also influences autophagy depending on the context, either promoting protective autophagy by targeting mTOR pathway regulators or enhancing chemosensitivity by suppressing key autophagy components like ATG5. New findings associate miR-155 with pyroptosis, necroptosis, and immune clearance via phagocytosis, though the mechanisms vary across pathways. In the tumor microenvironment, exosomal miR-155 spreads resistance traits, such as epithelial-mesenchymal transition, stemness, and survival signaling in adjacent cells. Therapeutic approaches include inhibition or restoration, tailored to isoform, tumor type, and network, with growing support for oligonucleotide-based therapies, nanoparticle delivery, and combination treatments. Overall, miR-155 is a powerful biomarker for chemoresistance and a promising therapeutic target, especially when strategies are isoform- and context-specific. This review adopts a mechanism-first approach to distinguish common resistance modules from true context-dependent exceptions, highlighting isoform specificity and translational relevance.