ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2023
Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- Efficacy and safety of immunotherapy in anaplastic thyroid carcinoma: a systematic review and meta-analysis.International journal of surgery (London, England) · 2026Pooled it
- Metabolic reprogramming-mediated therapeutic resistance in renal cell carcinoma: Mechanisms and targeted intervention strategies.iScience · 2026Review
- Cofilin1-driven cytoskeletal remodeling modulates pan-cancer CD8Cell reports. Medicine · 2026Article
- Endogenous metabolite signaling orchestrates tumor immune evasion.Cell insight · 2026Review
- In vivo CRISPR screens identify CBX4 as an epigenetic regulator for cancer immunotherapy.The Journal of clinical investigation · 2026Article
- Immune Escape in Renal Cell Carcinoma: Latest Research and Treatment Strategies.International journal of molecular sciences · 2026Review
- Insights into the mechanisms of drug resistance in renal cell carcinoma: from multi-omics perspective.International journal of surgery (London, England) · 2026Article
- Overcoming resistance to anti-PD-1/PD-L1 therapy in cancer.Cancer drug resistance (Alhambra, Calif.) · 2026Review
- The impact of p53 mutation on tumor immune evasion: mechanistic insights and clinical implications.Frontiers in immunology · 2026Review
- TCA cycle-derived oncometabolites in cancer and the immune microenvironment.Journal of biomedical science · 2025Review
- Exploring Metabolic and Immunological Biomarkers for Oral Squamous Cell Carcinoma: Potential Targets for Precision Therapy.Biology · 2025Review
- Decoding MHC loss: Molecular mechanisms and implications for immune resistance in cancer.Clinical and translational medicine · 2025Review
- Review
- Article
- PRMT5-Mediated Arginine Methylation of ACSL4 Attenuates Its Stability and Suppresses Ferroptosis in Renal Cancer.Research (Washington, D.C.) · 2025Article
- The role of B2M in cancer immunotherapy resistance: function, resistance mechanism, and reversal strategies.Frontiers in immunology · 2025Review
- Monocyte/Macrophage-Mediated Transport of Dual-Drug ZIF Nanoplatforms Synergized with Programmed Cell Death Protein-1 Inhibitor Against Microsatellite-Stable Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Programmed death receptor (PD-)1/PD-ligand (L)1 in urological cancers : the "all-around warrior" in immunotherapy.Molecular cancer · 2024Review
- Tumor ABCC4-mediated release of PGE2 induces CD8International journal of biological sciences · 2024Article
- The Tricarboxylic Acid Cycle Metabolites for Cancer: Friend or Enemy.Research (Washington, D.C.) · 2024Review
Corrections and comments
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Authors and funding
21 authors at 7 institutions in 2 countries.
Funding
Abstract
The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of β2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.