Lipid droplets restrict phagosome formation in antifungal immunity.

Lipid droplets (LDs) are intracellular organelles that can be induced and interact with phagosomes during the process of pathogen phagocytosis in macrophages. However, the function of LDs in phagocytosis remains elusive. Here, we unveil the role of LDs in modulating phagosome formation via a fungal infection model. Specifically, LD accumulation restricted the degree of phagosome formation and protected macrophages from death. Mechanistically, LD formation competitively consumed the intracellular endoplasmic reticulum membrane and altered RAC1 translocation and GTPase activity, which resulted in limited phagosome formation in macrophages during fungal engulfment. Mice with Hilpda-deficient macrophages were more susceptible to the lethal sequelae of systemic infection with C. albicans. Notably, administration of the ATGL inhibitor atglistatin improved host outcomes in disseminated fungal infections. Taken together, our study elucidates the mechanism by which LDs control phagosome formation to prevent immune cell death and offers a potential drug target for the treatment of C. albicans infections.