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The long-standing paradigm that foam cells are cholesterol-laden derives from atherosclerosis research. We previously showed that, in tuberculosis, foam cells surprisingly accumulate triglycerides. Here, we utilized bacterial (Mycobacterium tuberculosis), fungal (Cryptococcus neoformans), and human papillary renal cell carcinoma (pRCC) models to address the need for a new explanation of foam cell biogenesis. We applied mass spectrometry-based imaging to assess the spatial distribution of storage lipids relative to foam-cell-rich areas in lesional tissues, and we characterized lipid-laden macrophages generated under corresponding in vitro conditions. The in vivo data and the in vitro findings showed that cryptococcus-infected macrophages accumulate triglycerides, while macrophages exposed to pRCC-conditioned-medium accumulated both triglycerides and cholesterol. Moreover, Cryptococcus- and Mycobacterium-infected macrophages accumulated triglycerides in different ways. Collectively, the data show that the molecular events underlying foam cell formation are specific to disease and microenvironment. Since foam cells are potential therapeutic targets, recognizing that their formation is disease-specific opens new biomedical research directions.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf038","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T13:59:54Z","timestamp":1743429594000},"page":"1358-1369","source":"Crossref","is-referenced-by-count":3,"title":["Cryptococcosis, tuberculosis, and a kidney cancer fail to fit the atherosclerosis paradigm for foam cell lipid content"],"prefix":"10.1093","volume":"214","author":[{"given":"Valentina","family":"Guerrini","sequence":"first","affiliation":[{"name":"Public Health Research Institute, Rutgers Biomedical and Health Sciences , Newark, NJ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan","family":"Prideaux","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Texas Medical Branch , Galveston, TX,","place":["United 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