ArticleInternational journal of biological sciences2026
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.
Article in International journal of biological sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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