Targeting the MicroRNA-Autophagy Axis: Emerging Advances in Cancer Nanotherapeutics.

Abstract

Cancer remains a major clinical challenge due to persistent therapy resistance, despite significant treatment advances. While chemotherapy often induces initial regression, tumors adapt through complex mechanisms, with autophagy playing a pivotal role. As a conserved cytoplasmic turnover pathway, autophagy protects tumor cells under stress by recycling damaged components and reducing drug toxicity. However, it is also paradoxically capable of triggering autophagic cell death when activated excessively. Importantly, the balance is intricately fine-tuned by short non-coding miRNAs, which orchestrate the regulation of autophagy-related genes (ATGs), thereby influencing cancer cell survival and shaping response to chemotherapy. Although several miRNA-based therapeutics have advanced into preclinical and early clinical testing, most target canonical oncogenic signaling or immune modulation, while the autophagy-specific dimension remains largely unexplored, leaving a translational gap. In this review, we highlight the emerging role of the miRNA-autophagy axis in resistance and propose it as a promising frontier for therapeutic intervention. We further suggest that leveraging miRNA-based autophagy modulation with nanodrugs and conventional therapies could provide a multimodal framework to overcome resistance, reduce toxicity, and advance precision cancer treatment.