ArticleCell death & disease2025
Oncometabolite fumarate facilitates PD-L1 expression and immune evasion in clear cell renal cell carcinoma.
Article in Cell death & disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Metabolic regulation of calcium homeostasis via SERCA succination.Science advances · 2026Article
- The role of HIF-1α in innate immune mechanisms and autoimmunity: A double-edged sword.The Journal of biological chemistry · 2026Review
- Exploratory Multi-Level Analysis of the HIF Axis in Clear-Cell Renal Cell Carcinoma and Evaluation of GN44028 as an Experimental HIF Pathway-Modulating Compound.International journal of molecular sciences · 2026Article
- Hypoxia-driven tumor immune escape: mechanisms and therapeutic opportunities.Frontiers in immunology · 2026Review
- Nanoplatform-Mediated Remodeling of the Immune Microenvironment in Renal Cell Carcinoma.International journal of nanomedicine · 2026Review
- Therapeutic Potential of Fingolimod and Dimethyl Fumarate in Preclinical Pancreatic Cancer Models.Oncology research · 2026Article
- Immunometabolism: crosstalk with tumor metabolism and implications for cancer immunotherapy.Molecular cancer · 2025Review
- Comprehensive linkage between molecular biology and imaging radiomics for thyroid nodules.World journal of radiology · 2025Article
- Tumour- and Non-Tumour-Associated Factors That Modulate Response to PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer.Cancers · 2025Review
- Gut microbiota: a promising new target in immune tolerance.Frontiers in immunology · 2025Review
- GDF15 orchestrates mitochondrial-immune crosstalk via SMAD7-HIF-1α-PKM2 cascade to attenuate septic liver injury.Frontiers in immunology · 2025Article
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9 authors.
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Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), with a rising incidence worldwide. However, the mechanisms by which ccRCC evades immune surveillance remain incompletely understood. Our findings indicate that fumarate hydratase (FH) expression is significantly downregulated in ccRCC, resulting in fumarate accumulation, which is correlated with a poor prognosis in ccRCC patients. RNA sequencing analysis suggests that dimethyl fumarate (DMF), an FDA-approved fumarate analogue, may impact tumor immunity. Our further investigation reveals that both DMF and the FH inhibitor (FHIN1) can promote immune evasion in ccRCC by upregulating PD-L1. Pre-treatment of tumor cells with DMF notably inhibits the cytotoxic effect of T cells. Mechanistically, fumarate induces PD-L1 expression through succination of HIF-1α at C800, facilitating its interaction with importin α3, p300, and PKM2, which promotes HIF-1α nuclear localization and transcriptional activity. Moreover, combining DMF with PD-L1 blockade therapy significantly enhances the efficacy of immunotherapy and prolongs the survival of tumor-bearing mice. Taken together, our study elucidates a mechanism by which FH downregulation promotes immune evasion through the fumarate-HIF-1α/p300/PKM2-PD-L1 axis, providing a novel target, drug, and strategy to improve immunotherapy for ccRCC.
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