Tumor-derived progranulin reprograms immunosuppressive macrophages via cholesterol efflux in oral squamous cell carcinoma

Abstract Background The immunosuppressive tumor microenvironment (TME) contributes to poor prognosis in oral squamous cell carcinoma (OSCC), with tumor-associated macrophages (TAMs) playing a pivotal role. However, the underlying metabolic mechanisms that drive TAM polarization remain unclear. Methods We performed integrated single-cell RNA sequencing (scRNA-seq) on primary OSCC tumors (n = 3) and validated findings in 77 head and neck squamous cell carcinoma (HNSCC) samples across five public datasets. The role of tumor-derived progranulin (PGRN) in TAM reprogramming was examined using genetic knockdown, pharmacologic inhibition of PGRN–SORT1 interaction, and activation of downstream PPARγ signaling in vitro and in vivo. Results A malignant epithelial subpopulation highly expressing PGRN was identified, which reprogrammed TAMs via SORT1-mediated dependent signaling. Mechanistically, PGRN–SORT1 interaction induced PPARγ/LXRα activation, upregulated cholesterol efflux transporters ABCA1/ABCG1 (p < 0.001), and reduced intracellular r cholesterol levels in macrophages. This metabolic rewiring led to an immunosuppressive TAM phenotype, with increased secretion of IL-6, IL-10, and TGFβ. PGRN knockdown or SORT1 inhibition restored cholesterol retention, reduced TAM infiltration, and increased the CD86⁺/CD206⁺ ratio in vivo. Notably, PPARγ agonism with rosiglitazone reinstated immunosuppression in PGRN-deficient tumors, confirming the dependence on this signaling axis. Conclusion Tumor-derived PGRN reprograms TAMs via SORT1-mediated cholesterol efflux and downstream PPARγ/LXRα activation, promoting an immunosuppressive TME in OSCC. Targeting the PGRN–SORT1–PPARγ axis may represent a promising immunometabolic approach to overcome immune resistance and improve OSCC outcomes.