Lipid droplets in the tumor microenvironment: Biogenesis, functional diversity, and therapeutic targeting

Historically regarded as inert energy storage depots, lipid droplets (LDs) are now recognized as dynamic organelles that regulate diverse cellular processes, including membrane biosynthesis, stress adaptation, signal transduction, and metabolic homeostasis. In cancer, tumor cells hijack LD-driven metabolic pathways to fuel uncontrolled proliferation, migration, and therapy resistance, thereby promoting tumor progression. Emerging evidence suggests that tumor-associated immune cells similarly utilize LD-mediated mechanisms to reinforce immunosuppression and support tumor progression. However, the intercellular crosstalk and regulatory networks coordinated by LD-associated effectors across malignant and immune cells have not been systematically explored. This review synthesizes current knowledge on LD biogenesis, spatiotemporal distribution, and microenvironment-dependent regulation in both tumor cells and tumor-infiltrating immune cells. We focus on how LD-associated proteins shape the immunosuppressive tumor microenvironment and drive oncogenic progression. Furthermore, we highlight novel therapeutic strategies targeting LD metabolism to simultaneously disrupt tumor survival and counteract immune cell-mediated protumorigenic effects. Finally, we discuss the challenges and future directions of LD-targeted therapies, particularly in combination with immunotherapies, to provide a roadmap for next-generation anticancer interventions.