Unraveling the Mechanisms of Chemoresistance in Gastric Cancer: Insights and Emerging Research Strategies.

Abstract

Purpose of review: Gastric cancer (GC) is a leading cause of cancer death globally. Platinum‑based drugs, fluoropyrimidines, and docetaxel are standard for advanced disease, but intrinsic and acquired resistance limit the efficacy. This review summarizes chemoresistance mechanisms, focusing on the roles of various cell death pathways in GC chemoresistance, as well as the involvement of non-coding RNAs (ncRNAs) in modulating drug resistance through multiple regulatory mechanisms. We also describe models for establishing resistant cell lines (stepwise dose escalation, high-dose intermittent pulse selection, gene transfection).

Recent findings: Emerging evidence has identified intricate crosstalk among apoptosis, autophagy, and ferroptosis in chemoresistant GC cells. Aberrant expression of Bcl‑2 family members, protective autophagic flux, and suppression of ferroptosis (e.g., via SLC7A11/GPX4) are key drivers. Concurrently, ncRNAs particularly microRNAs, long non‑coding RNAs, and circular RNAs have been shown to modulate resistance by targeting death‑related genes, altering drug efflux, or reprogramming the tumor microenvironment. Preclinical agents that modulate ferroptosis or ncRNA expression demonstrate promising chemosensitizing effects. Collectively, the interplay between cell death pathways and the ncRNA regulatory networks profoundly influences chemoresistance in GC. Deciphering these mechanisms offers a theoretical basis for developing biomarkers and combination strategies that overcome resistance, ultimately improving patient outcomes.