Long noncoding RNAs as master regulators of autophagy in cancer: Implications for chemoresistance and therapeutic sensitization.

Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators of autophagy, a fundamental cellular process that maintains homeostasis under stress but also contributes to cancer progression and therapeutic resistance. Recent studies reveal that lncRNAs orchestrate autophagy through diverse mechanisms, including acting as competing endogenous RNAs (ceRNAs), directly interacting with core autophagy machinery such as Beclin1 and ATG proteins, or modulating key signaling pathways like PI3K/AKT/mTOR, Wnt/β-catenin, and HIF-1α. By fine-tuning autophagic activity, lncRNAs shape tumor cell survival, proliferation, and response to chemotherapy, targeted therapy, and radiotherapy. Importantly, the impact of autophagy is highly context-dependent: in some settings, lncRNA-driven autophagy promotes drug resistance and tumor progression, whereas in others, autophagy induction exerts tumor-suppressive effects. Targeting the lncRNA-autophagy axis therefore offers dual opportunities: inhibiting pro-autophagic lncRNAs to overcome chemoresistance, or restoring anti-autophagic lncRNAs to sensitize tumors to treatment. Advances in RNA-based therapeutics and delivery platforms, coupled with small-molecule autophagy modulators and immunotherapy, provide new avenues for translational applications. In this review, we summarize current knowledge of lncRNA-mediated autophagy in cancer, highlight its role in therapeutic resistance and sensitization, and discuss challenges and opportunities for clinical translation.