Drug Resistance and Therapeutic Reversal Strategies in Ovarian, Cervical, and Endometrial Cancers.

Gynecological cancers (GCs) remain a leading cause of cancer-related mortality among women worldwide. Their high mortality rate is strongly linked to resistance to chemotherapy and targeted therapy, which significantly affects treatment efficacy and patient survival. This review summarizes the status of drug resistance in ovarian cancer (OC), cervical cancer (CC), and endometrial cancer (EC), and elucidates their multi-level drug resistance mechanisms in five aspects: DNA damage repair (DDR) dysregulation, core signaling pathways dysregulation, epigenetic dysregulation, transmembrane drug transport dysregulation, and tumor microenvironment (TME) dysregulation. Based on these mechanisms, this review synthesizes six corresponding reversal strategies: DDR inhibition, core signaling pathway intervention, epigenetic regulation, drug transport protein regulation, tumor microenvironment (TME) interventions, and emerging technologies applications. The evidence discussed ranges from preclinical studies to clinical trials. By integrating key findings on the multifaceted mechanisms of drug resistance and associated reversal approaches in GCs, this review also discusses the limitations of current therapies and provides perspectives for further mechanistic investigation and the development of novel treatment strategies.