Long Noncoding RNAs as Master Regulators of Autophagy in Cancer: Implications for Chemoresistance and Therapeutic Sensitization

Jan 4, 2026Critical reviews in oncology/hematology

Long Noncoding RNAs as Key Controllers of Cell Recycling in Cancer Linked to Drug Resistance and Treatment Response

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Long noncoding RNAs (lncRNAs) are vital regulators of autophagy, a process that can both support cancer progression and enhance therapeutic resistance.

LncRNAs may regulate autophagy through mechanisms such as acting as competing endogenous RNAs or interacting directly with key autophagy proteins.
They can modulate important signaling pathways, including PI3K/AKT/mTOR and Wnt/β-catenin, influencing tumor cell behavior.
Autophagy's effects are context-dependent; lncRNA-driven autophagy may either promote drug resistance and tumor progression or exert tumor-suppressive effects.
Targeting the relationship between lncRNAs and autophagy could help overcome chemoresistance or enhance the effectiveness of cancer therapies.
Recent advancements in RNA-based treatments and small-molecule autophagy modulators may lead to new options for cancer treatment.

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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.

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Long Noncoding RNAs as Master Regulators of Autophagy in Cancer: Implications for Chemoresistance and Therapeutic Sensitization

Abstract

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