Autophagy initiation inhibition combined with chemotherapy reverses drug resistance in oral cancer.

Oral cancer, a common malignancy of the head and neck, remains therapeutically challenging largely due to the frequent development of chemotherapy resistance. Autophagy, a key cellular stress-response pathway, contributes to oral cancer cell survival and drug tolerance under therapeutic pressure. Emerging evidence indicates that targeting the initiation phase of autophagy—particularly when combined with conventional agents such as cisplatin—may help reverse resistance and improve treatment efficacy. In this review, we summarize the molecular mechanisms governing autophagy initiation, highlight key actionable targets, and discuss the synergistic effects observed when autophagy inhibitors are paired with chemotherapeutic drugs. We place particular emphasis on newly developed initiation-stage inhibitors, bioactive natural products, and nanotechnology-enabled formulations that show potential for overcoming chemoresistance in oral cancer. By integrating recent advances, this article aims to provide a mechanistic framework and translational considerations to support the development of more precise therapeutic strategies for chemotherapy-resistant oral cancer.