ArticleJournal of translational medicine2026
Tumor-derived progranulin promotes macrophage cholesterol efflux and associated immunosuppressive features in oral squamous cell carcinoma.
Article in Journal of translational medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundCholesterol efflux is increasingly recognized as an important regulator of macrophage polarization and immunosuppressive features; however, the tumor-derived signals that govern this process in oral squamous cell carcinoma (OSCC) remain poorly defined.
methodsWe performed integrated single-cell RNA sequencing (scRNA-seq) on primary OSCC tumors (n = 3) and validated the findings in 77 head and neck squamous cell carcinoma (HNSCC)-related samples across five public datasets. The role of tumor-derived progranulin (PGRN) in macrophage cholesterol efflux and associated phenotypic changes was examined using genetic knockdown, pharmacologic inhibition of the PGRN-SORT1 interaction, and activation of downstream PPARγ signaling in vitro and in vivo.
resultsA malignant epithelial subpopulation with high PGRN expression was identified and associated with macrophage cholesterol efflux regulation through a prominent SORT1-associated signaling axis. Functional assays suggested that tumor-derived PGRN promoted a SORT1-linked PPARγ-LXRα-ABCA1/ABCG1 program, accompanied by enhanced cholesterol efflux and reduced intracellular cholesterol levels in macrophages. This metabolic rewiring was associated with immunosuppressive macrophage features, accompanied by increased secretion of IL-6, IL-10, and TGF-β. PGRN knockdown or SORT1 inhibition attenuated cholesterol efflux and increased intracellular cholesterol retention in vitro. In vivo, PGRN knockdown was associated with changes in macrophage polarization-related features, as reflected by an increased CD86
conclusionTumor-derived PGRN is associated with immunosuppressive macrophage features in OSCC, at least in part through a SORT1-linked cholesterol efflux program involving downstream PPARγ-LXRα activation. These findings support a role for the PGRN-SORT1-associated axis as a potential immunometabolic pathway associated with macrophage cholesterol efflux and phenotypic features in OSCC.
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