MINDY1 drives metabolic-immune crosstalk via OGT-UGP2-UDPG axis to promote immunosuppressive macrophage reprogramming.

The efficacy of immune checkpoint blockade is limited in hepatocellular carcinoma (HCC) due to tumor-intrinsic mechanisms. Here we identify the deubiquitinase MINDY1 as a central regulator of metabolic-immune crosstalk that drives immunotherapy resistance in HCC. MINDY1 is significantly upregulated in immunotherapy non-responders and correlates with poor prognosis and increased M2-like macrophage infiltration. Mechanistically, MINDY1 stabilizes O-GlcNAc transferase (OGT) by removing K48-linked ubiquitin chains, thereby enhancing O-GlcNAcylation of uridine diphosphate glucose pyrophosphorylase 2 (UGP2) at T152. This modification promotes UGP2 enzymatic activity and increases uridine diphosphate glucose (UDPG) synthesis and extracellular accumulation. Tumor-derived UDPG acts as an extracellular immunometabolite that directly binds to PPARγ in macrophages, promoting its nuclear translocation and transcriptional activation. UDPG-driven PPARγ signaling enhances fatty acid oxidation and induces M2-like polarization, suppressing CD8+ T-cell cytotoxicity and establishing an immunosuppressive tumor microenvironment. Targeting MINDY1 remodels macrophage metabolism, restores CD8+ T-cell effector function, and significantly enhances anti-PD-1 efficacy in vivo. Our findings uncover a previously unrecognized mechanism that links tumor proteostasis to immune suppression and identify MINDY1 as a promising therapeutic target for overcoming immunotherapy resistance in HCC.