This study presents OrgaPlexing, a multi-spectral organelle imaging technique that maps six key metabolic organelles and their interactions in macrophages. The research reveals that lipid droplets (LDs) are central to inflammatory lipid metabolism in macrophages, forming three- and four-way interactions with other organelles. These interactions are crucial for fatty acid supply and efflux from LDs, supporting inflammatory lipid mediator synthesis. The study shows that macrophages form functional multi-organelle units to adapt their metabolism and provide a strategy to identify organelle-metabolic signaling hubs. Organelle communication is essential for connecting metabolic pathways, with lipid metabolism involving LDs, mitochondria, peroxisomes, lysosomes, and the endoplasmic reticulum. The study highlights the dynamic coordination of organelle systems in macrophages during metabolic switches, emphasizing the role of LDs in inflammatory responses. The findings demonstrate that macrophages use clustered organelles for lipid trafficking, with LDs serving as reservoirs for arachidonic acid, a precursor for prostaglandin E2 (PGE2) production. The study also identifies MIGA2 as a key regulator of LD fuelling and PGE2 production, and shows that mitochondrial fission regulator DRP1 controls the assembly of multi-organelle units and PGE2 production. The research underscores the importance of organelle interactions in metabolic adaptation and immune responses, providing insights into the regulation of lipid metabolism and inflammatory signaling in macrophages.This study presents OrgaPlexing, a multi-spectral organelle imaging technique that maps six key metabolic organelles and their interactions in macrophages. The research reveals that lipid droplets (LDs) are central to inflammatory lipid metabolism in macrophages, forming three- and four-way interactions with other organelles. These interactions are crucial for fatty acid supply and efflux from LDs, supporting inflammatory lipid mediator synthesis. The study shows that macrophages form functional multi-organelle units to adapt their metabolism and provide a strategy to identify organelle-metabolic signaling hubs. Organelle communication is essential for connecting metabolic pathways, with lipid metabolism involving LDs, mitochondria, peroxisomes, lysosomes, and the endoplasmic reticulum. The study highlights the dynamic coordination of organelle systems in macrophages during metabolic switches, emphasizing the role of LDs in inflammatory responses. The findings demonstrate that macrophages use clustered organelles for lipid trafficking, with LDs serving as reservoirs for arachidonic acid, a precursor for prostaglandin E2 (PGE2) production. The study also identifies MIGA2 as a key regulator of LD fuelling and PGE2 production, and shows that mitochondrial fission regulator DRP1 controls the assembly of multi-organelle units and PGE2 production. The research underscores the importance of organelle interactions in metabolic adaptation and immune responses, providing insights into the regulation of lipid metabolism and inflammatory signaling in macrophages.