Tumor-derived progranulin promotes macrophage cholesterol efflux and associated immunosuppressive features in oral...

Cholesterol 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.

We 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.

A 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⁺/CD206⁺ ratio. Notably, PPARγ agonism with rosiglitazone partially restored these phenotypic changes in PGRN-deficient tumors, supporting the involvement of this signaling axis.

Tumor-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.