Inhibition of glycolysis enhances the efficacy of immunotherapy via PDK-mediated upregulation of PD-L1.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:38832951", "kind": "science-record", "revision": 4, "content_hash": "sha256:dae733480b7385649786feb7fd6f138e8579dc408df1947e1704addc327c17e9", "created_at": "2026-11-01T19:20:47Z", "updated_at": "2026-11-01T22:54:26Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Inhibition of glycolysis enhances the efficacy of immunotherapy via PDK-mediated upregulation of PD-L1.", "doi": "10.1007/s00262-024-03735-0", "pmid": "38832951", "authors": ["Ruizhi Zhang", "Gan Mao", "Yu Tang", "Chong Li", "Yisong Gao", "Wenxiang Nie", "Tianyu Song", "Suao Liu", "Peng Zhang", "Kaixiong Tao", "Wei Li"], "journal": "Cancer immunology, immunotherapy : CII", "year": 2024, "abstract": "BACKGROUND: Immunotherapy for gastric cancer remains a challenge due to its limited efficacy. Metabolic reprogramming toward glycolysis has emerged as a promising avenue for enhancing the sensitivity of tumors to immunotherapy. Pyruvate dehydrogenase kinases (PDKs) play pivotal roles in regulating glycolysis. The importance of PDKs in the context of gastric cancer immunotherapy and their potential as therapeutic targets have not been fully explored.\nMETHODS: PDK and PD-L1 expression was analyzed using data from the GSE66229 and The Cancer Genome Atlas (TCGA) cohorts. Additionally, the Immune Checkpoint Blockade Therapy Atlas (ICBatlas) database was utilized to assess PDK expression in an immune checkpoint blockade (ICB) therapy group. Subsequently, the upregulation of PD-L1 and the enhancement of anticancer effects achieved by targeting PDK were validated through in vivo and in vitro assays. The impact of PDK on histone acetylation was investigated using ChIP‒qPCR to detect changes in histone acetylation levels.\nRESULTS: Our analysis revealed a notable negative correlation between PD-L1 and PDK expression. Downregulation of PDK led to a significant increase in PD-L1 expression. PDK inhibition increased histone acetylation levels by promoting acetyl-CoA generation. The augmentation of acetyl-CoA production and concurrent inhibition of histone deacetylation were found to upregulate PD-L1 expression in gastric cancer cells. Additionally, we observed a significant increase in the anticancer effect of PD-L1 antibodies following treatment with a PDK inhibitor.\nCONCLUSIONS: Downregulation of PDK in gastric cancer cells leads to an increase in PD-L1 expression levels, thus potentially improving the efficacy of PD-L1 immune checkpoint blockade therapy.", "claims": [{"id": "claim-method", "statement": "For comparisons between two groups, two-tailed and unpaired Student’s t-tests were applied. To analyze the differences among multiple groups, we utilized one-way ANOVA followed by Sidak’s multiple comparison test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38832951", "locator": "sections[16] \"Statistical analysis\" paragraph 2", "quote": "For comparisons between two groups, two-tailed and unpaired Student’s t-tests were applied. To analyze the differences among multiple groups, we utilized one-way ANOVA followed by Sidak’s multiple comparison test."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Public datasets used in the study could be downloaded in online repositories. The original data presented in the study can be found in the article/supplementary material.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38832951", "locator": "sections[28] \"Data availability\" paragraph 2", "quote": "Public datasets used in the study could be downloaded in online repositories. The original data presented in the study can be found in the article/supplementary material."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Downregulation of PDK in gastric cancer cells leads to an increase in PD-L1 expression levels, thus potentially improving the efficacy of PD-L1 immune checkpoint blockade therapy.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:38832951", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "Downregulation of PDK in gastric cancer cells leads to an increase in PD-L1 expression levels, thus potentially improving the efficacy of PD-L1 immune checkpoint blockade therapy."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Downregulation of PDK in gastric cancer cells leads to an increase in PD-L1 expression levels, thus potentially improving the efficacy of PD-L1 immune checkpoint blockade therapy.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:38832951"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE66229"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE66229"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:38832951", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1007/s00262-024-03735-0", "sha256": "sha256:f44198ed148d5dfdf2e9bd6d971877b5740ffc8bfc9ee683646a5c347e19d74c", "bytes": 47441, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1007/s00262-024-03735-0", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC11150234", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE66229", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE66229", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE66229", "version": null, "note": "Public datasets used in the study could be downloaded in online repositories. The original data presented in the study can be found in the article/supplementary material.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Public datasets used in the study could be downloaded in online repositories. 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