Mechanisms of chemoresistance in gastric cancer: interplay between microRNAs and the tumor microenvironment

Chemoresistance remains a major barrier to durable disease control in gastric cancer, limiting the effectiveness of perioperative and palliative systemic therapies. Increasing evidence indicates that resistance is driven by a complex interplay between tumor-intrinsic adaptations and tumor microenvironment-mediated survival pathways. Although chemoresistance can be innate or acquired, a variety of mechanisms could coexist within the tumor, with various processes acting synergistically. MicroRNAs, as key post-transcriptional regulators, have emerged as central modulators of these resistance networks. This review summarizes the principal mechanisms of chemoresistance in gastric cancer and synthesizes current evidence on how microRNAs-derived from tumor cells and the tumor microenvironment-promote or reverse resistance to commonly used chemotherapeutic agents and targeted therapy/immunotherapies, highlighting therapeutic opportunities. Evidence was organized by mechanism (drug transport and metabolism, DNA damage response, apoptosis and survival signaling, autophagy, epithelial-to-mesenchymal transition/cancer stem cell plasticity, and immune escape) and by drug class.