Targeting Mitochondrial PD-L1 O-GlcNAcylation to Sensitize HBV-Related HCC to Immunotherapy: Modulating Golgi-mitochondrial Crosstalk and mTOR/PGC-1α-Driven Mitochondrial Biogenesis to Overcome Resistance.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with chronic hepatitis B virus (HBV) infection representing its foremost risk factor. Although programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) have entered clinical practice, response rates in HBV-related HCC remain limited, underscoring the urgent need for mechanism-based strategies to overcome intrinsic resistance and improve immune checkpoint blockade (ICB) efficacy by exploiting noncanonical PD-L1 functions. Here, we identify a non-canonical pathway in which the HBV-encoded X protein (HBx) drives O-GlcNAcylation (O-GlcNAc) of PD-L1 at S283 and T285, thereby promoting PD-L1 mitochondrial translocation via the GOLPH3/Drp1 axis. Mitochondrial PD-L1 (mtPD-L1) hijacks Golgi-mitochondria communication to activate the mTOR/PGC-1α axis, enhance mitochondrial biogenesis and translation, and reprogram cellular energy metabolism, ultimately conferring resistance to anti-PD-L1 antibody (αPD-L1) therapy in HBV-related HCC. Pharmacological inhibition of O-GlcNAcylation with OSMI-1 disrupts this mtPD-L1 regulatory axis, restores mitochondrial homeostasis, and sensitizes HBV-related HCC to αPD-L1 therapy. Collectively, these findings identify O-GlcNAcylated mtPD-L1 as a previously unrecognized immunometabolic checkpoint and establish the mtPD-L1-mTOR/PGC-1α axis as a key mechanism linking mitochondrial biogenesis to immunotherapy resistance. This study provides a rationale for combining αPD-L1 with OSMI-1-mediated O-GlcNAcylation inhibition as a therapeutic strategy to improve immunotherapy sensitivity in HBV-related HCC.