E3 ubiquitin ligases orchestrate chemo-resistance in gastrointestinal malignancies: from DNA damage response to therapeutic targeting.

Therapy resistance in gastrointestinal tumors remains a critical challenge in clinical oncology, severely compromising therapeutic efficacy and long-term patient survival. E3 ubiquitin ligases, as core enzymes involved in the protein ubiquitination process, have been demonstrated to play indispensable roles in regulating key biological processes in tumor cells, including DNA damage repair, cell cycle progression, apoptosis, cancer stem cell maintenance, and immune evasion. Additionally, E3 ligases are key regulators of resistance to multiple anticancer strategies, such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy. This review systematically summarizes the functions and mechanisms of E3 ligases in DNA damage response and cancer therapy resistance, and further highlight recent advances in therapeutic approaches by targeting specific E3 ligases. Notably, combining E3 inhibitors with existing anticancer therapies may substantially enhance treatment responses and improve patient prognosis, providing a solid theoretical basis for future clinical applications.