{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T20:34:31Z","timestamp":1794170071892,"version":"4.8.0"},"reference-count":111,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare, aggressive malignancy with limited therapeutic options and poor prognosis. Despite immune checkpoint inhibitors (ICIs) showing efficacy in other cancers, responses in FH-deficient RCC remain suboptimal. Metabolic remodeling, particularly the Warburg effect-driven glycolysis, is implicated in immune evasion and tumor progression, highlighting the need for predictive biomarkers and combinatorial strategies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We integrated 41 single-cell RNA sequencing (scRNA-Seq) datasets (19 malignancies, 405 patients, 1,220,365 cells) to develop a glycolytic signature (Glyc.Sig). Validation included pan-cancer transcriptomic analysis (30 cancer types, n=10,154), CRISPR screening data (4 cancers), and clinical immunotherapy cohorts (5 cancers, n=921). LDHA was identified as a top-ranked immune-resistant candidate through CRISPR screening analysis, validated via immunoblotting and immunohistochemistry in Renji Hospital cohorts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Glyc.Sig exhibited a robust inverse correlation between glycolytic activity and ICI efficacy across malignancies. It outperformed conventional biomarkers in predicting immunotherapy outcomes. CRISPR screening prioritized LDHA, a key glycolytic enzyme, as a target to enhance ICI response. Clinical validation confirmed elevated LDHA expression in FH-deficient RCC tumor tissues, which may correlate with immunosuppressive microenvironments and resistance to ICIs. Combinatorial LDHA inhibition and ICI treatment may demonstrate synergistic antitumor effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This study establishes Glyc.Sig as a dual diagnostic-predictive biomarker system, linking glycolytic reprogramming to immune evasion. Comparative validation revealed its enhanced predictive capacity for ICI responsiveness relative to existing molecular signatures. LDHA inhibition emerges as a promising strategy to overcome ICI resistance in FH-deficient RCC and other glycolytic tumors. These findings underscore the therapeutic potential of targeting cancer metabolism to optimize immunotherapy efficacy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1666121","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T05:30:03Z","timestamp":1759469403000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Integrated multi-omics analysis reveals a glycolytic signature that predicts pan-cancer immune checkpoint inhibitor response and LDHA as a combinatorial target in fumarate hydratase-deficient renal cell 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