Epithelial HSD11β2 as an immunometabolic checkpoint in head and neck cancer: Restoring local steroid inactivation reinvigorates T cell immunity.

Systemic glucocorticoid (GC) effects in oncology are well recognized; however, the role of local GC metabolism within the tumor microenvironment remains poorly defined. Epithelial 11β-hydroxysteroid dehydrogenase 2 (HSD11β2), which inactivates GCs, may regulate GC-driven immune suppression in head and neck squamous cell carcinoma (HNSCC). We combined clinical survival analyses from an HNSCC cohort (ORIEN) with mechanistic studies in CRISPR/Cas9 Hsd11β2-knockout (KO) cell lines, an epithelial-specific Hsd11β2 conditional KO (eHSD-/-) mouse model, and an orthotopic model with exogenous GC exposure. Immune profiling, GC quantification, and transcriptomic analyses were performed. Apigenin was evaluated as a pharmacologic inducer of HSD11β2. In the retrospective HNSCC cohort, GC (Prednisolone) exposure was associated with inferior overall survival (HR = 2.1, 95% CI 1.3-3.46; p < 0.0001). Loss of epithelial Hsd11β2 increased active GC bioavailability, enhanced tumor proliferation, and suppressed T cell effector function, accompanied by expansion of immunosuppressive myeloid populations. Transcriptomic analyses revealed activation of GC-responsive and pro-tumor pathways with concurrent depletion of lymphocyte activation signatures. Pharmacologic induction of HSD11β2 with apigenin reduced active GC levels, suppressed tumor growth, and restored T cell function. Notably, apigenin retained partial antitumor effects in Hsd11β2 KO models, indicating both HSD11β2 dependent and complementary mechanisms. These findings support a role for local GC metabolism as an immunometabolic checkpoint in HNSCC. In experimental models, restoring epithelial GC inactivation via HSD11β2 reduces immune suppression and restrains tumor progression. Pharmacologic induction of HSD11β2 represents a promising strategy to counter steroid-driven immune evasion and may enhance responses to immunotherapy.