Crosstalk between lipid droplets and autophagy in cancer: A nexus for therapeutic targeting

Metabolic reprogramming is a cornerstone of cancer cell adaptation to the demanding tumor microenvironment, requiring fine-tuned control over energy, lipid metabolism, and stress responses. Central to this adaptation is the profound and bidirectional interplay between two key cellular processes: lipid storage in lipid droplets (LDs) and cellular recycling via autophagy. LDs are dynamic organelles that have emerged as critical metabolic and signaling hubs, extending far beyond their role as simple lipid depots. Autophagy, a fundamental degradation system, supplies essential metabolites during stress by engulfing cellular material in autophagosomes. These pathways are deeply intertwined: LDs not only provide lipids and proteins for autophagosome formation but are also selectively targeted for degradation by autophagy in a process known as lipophagy. This degradation releases free fatty acids that fuel mitochondrial β-oxidation, enabling cancer cells to withstand hypoxic and nutrient-poor conditions. Moreover, lipophagy prevents lipotoxicity by eliminating excess lipids, thus maintaining cellular homeostasis. Here, we review the molecular mechanisms governing the LD-autophagy axis in cancer, discuss its pivotal roles in tumor progression, metastasis, and therapeutic resistance, and explore the promise of targeting this nexus for future cancer therapies. Unraveling this complex network provides not only a new paradigm for understanding cancer metabolism but also offers a compelling rationale for developing novel pharmacological agents to combat tumor metabolic plasticity and therapeutic resistance. • The LD-autophagy axis is a central hub for cancer metabolic plasticity. • The interplay is bidirectional: LDs support autophagosome biogenesis and are degraded by lipophagy. • Lipophagy fuels cancer progression, metastasis, and therapy resistance via FFA provision. • The molecular machinery involves Rab GTPases, receptors (Spartin), and CMA-assisted uncoating. • Targeting the LD-autophagy nexus is a promising pharmacological strategy for cancer therapy.