Chemoresistance in gynecologic cancers: mechanistic insights and emerging platforms to overcome drug failure

Abstract The most difficult hurdles associated with the treatment of gynecologic cancer (such as ovarian, cervical, and endometrial cancer) is chemoresistance, with ovarian cancer representing the most clinically challenging subtype due to frequent relapse and the development of platinum resistance. Although chemotherapy remains one of the most important approaches to the management of gynecologic cancer, a large portion of patients have a poor initial response or recurrence of the treatment-resistant disease, factors that influence the rate of survival. This review highlights the present understanding of biological, molecular, and micro-environmental mechanisms that cause chemoresistance in gynecologic cancers, with primary emphasis on ovarian cancer while drawing supportive comparisons with cervical and endometrial malignancies. Important mechanisms of chemoresistance like increased drug efflux, redox based detoxification, increased capability of repairing DNA, evading apoptosis, protection by tumor microenvironment, epithelial-mesenchymal transition, persistence of cancer stem cells, epigenetic reprogramming and exosome-based communication are discussed in an integrated and easily understandable style. In addition to the overview of these mechanisms, this review also brings out newer treatment approaches that may emerge to overcome drug failure, especially in platinum-resistant ovarian cancer. These approaches include drug efflux transporter inhibitors, redox and metabolic pathways modulators, DNA repair, epigenetics, immunotherapies, tumor microenvironment, nanotechnology-delivery systems, and exosome interventions. The development in artificial intelligence and multi-omics methods that can be used to predict treatment response and deliver personalized management are also discussed, highlighting their potential role in early identification of resistance and treatment stratification in ovarian cancer patients. Collectively, these insights may help to improve therapeutic decision-making, which could enhance chemotherapy responsiveness, and support durable clinical outcomes in ovarian and other gynecologic malignancies.