PRMT3 drives PD-L1-mediated immune escape through activating PDHK1-regulated glycolysis in hepatocellular carcinoma

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Март 6, 2025

Aberrant expression of programmed death ligand-1 (PD-L1) facilitates tumor immune evasion. Protein arginine methyltransferase 3 (PRMT3), a member type I PRMT family, mediates asymmetric dimethylarginine (ADMA) modification various substrate proteins. This study investigates the role PRMT3 in PD-L1-associated immunosuppression hepatocellular carcinoma (HCC). Hepatocyte-specific knockout Prmt3 significantly suppressed HCC progression DEN-CCL4-treated mice. Knockout cells markedly increased CD8+ T cell infiltration, and reduced lactate production tumors. interacted with pyruvate dehydrogenase kinase 1 (PDHK1), dimethylation PDHK1 at 363 368 residues its activity. The R363/368 K mutant or inhibition by JX06 blocked effect on production. treatment also attenuated tumor-promoting vitro vivo. Furthermore, RNA-seq analysis revealed that downregulates tumor-associated checkpoint, PD-L1, tissues. Chromatin immunoprecipitation (ChIP) assay demonstrated promotes lactate-induced PD-L1 enhancing direct binding histone H3 lysine 18 lactylation (H3K18la) to promoter. Tissue microarray showed positive correlation between patients. Anti-PD-L1 reversed PRMT3-induced growth restored infiltration. Our research links PRMT3-mediated metabolic reprogramming evasion, revealing PRMT3-PDHK1-lactate-PD-L1 axis may be potential target for improving efficacy immunotherapy HCC.

Язык: Английский

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Alternative Splicing: A Key Regulator in T cell Response and Cancer Immunotherapy

Pharmacological Research, Год журнала: 2025, Номер unknown, С. 107713 - 107713

Опубликована: Март 1, 2025

Язык: Английский

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PRMT5 inhibitors: Therapeutic potential in pancreatic cancer

Translational Oncology, Год журнала: 2025, Номер 55, С. 102366 - 102366

Опубликована: Март 30, 2025

Язык: Английский

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Capturing Unicorns: Targeting Cancers With TP53 Mutations, RAS Alterations Beyond G12C, and MTAP Loss—No Target Is Out of the Realm of Possibility

American Society of Clinical Oncology Educational Book, Год журнала: 2025, Номер 45(3)

Опубликована: Май 28, 2025

In cancer genomics, there is the realization that some very frequently mutated genes like TP53 or KRAS are extremely hard to approach from a therapeutic perspective. realm of treatment, development agents capable transforming these alterations into actionable targets would be capturing unicorns. These unicorns oncology—drugs targeting undruggable span various types—offer an exciting opportunity for histology-agnostic therapies. Among these, recent developments in mutations, alterations, and MTAP loss mark pivotal advancements innovative treatment strategies. which occur nearly every type, central tumorigenesis contribute resistance against conventional especially cancers pancreatic lung cancers, notoriously difficult target but now yielding promising avenues. Similarly, deleted such as lung, pancreatic, mesothelioma plays critical role cellular metabolism epigenetics, making its significant vulnerability tumor cells. Recent drug discovery provide broad foundation clinical testing drugs common mechanisms across diverse types, offering hope more universal treatment.

Язык: Английский

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Collateral lethality: A unique type of synthetic lethality in cancers

Pharmacology & Therapeutics, Год журнала: 2024, Номер 265, С. 108755 - 108755

Опубликована: Ноя. 23, 2024

Язык: Английский

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