Lipid droplets in the tumor microenvironment

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. 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.

LDs have evolved from being regarded merely as lipid storage organelles to being recognized as central regulators of tumor metabolic reprogramming and immune microenvironment modulation. Their formations–including neutral lipid synthesis, nucleation, and budding, regulated by key proteins such as DGAT and Seipin–not only provide energy reserves for tumor cells but also enable adaptation to microenvironmental stresses through dynamic membrane synthesis and the maintenance of lipid homeostasis.

LDs display notable metabolic plasticity that confers protective functions across diverse tumor types, while simultaneously shaping immunosuppressive phenotypes within the TME. For instance, they promote protumoral polarization of TAMs by enhancing lipid uptake, modulate CD8+ T cell exhaustion through lipid overload, coordinate Treg-mediated immunosuppression, and impair DC and MDSC functions via disrupted antigen presentation or excessive FAO. These multifaceted roles position LDs as critical metabolic–immune hubs, thereby prompting diverse therapeutic strategies. Such strategies include inhibiting lipid uptake receptors such as CD36 and MARCO, disrupting biogenesis enzymes including DGAT1/2 and ACAT1, and targeting LD-mitochondria contacts involving CPT1A and PLIN2.

Notably, preclinical studies demonstrate promising synergy when LD-targeted approaches are combined with immunotherapy.LDs represent a dynamic and context-dependent metabolic–immune interface in cancer. A deeper understanding of their biology, coupled with innovative therapeutic targeting strategies, could open new avenues for LD-based antitumor treatments. Such approaches may enhance patient survival and restore antitumor immunity.

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Reference
DOI: https://doi.org/10.1097/CM9.0000000000003916

About the authors
Xiu-Wu Bian, professor from Key Laboratory of Tumor Immunopathology, Ministry of Education of China

Yi-Fang Ping, professor from Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University)

Funding information
This research was supported by the Noncommunicable Chronic Diseases- National Science and Technology Major Project (No. 2024ZD0525301) and the National Natural Science Foundation of China (Nos. 82172808 and 82303334).