ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1666121
This article is part of the Research TopicImmune Predictive and Prognostic Biomarkers in Immuno-Oncology: Refining the Immunological Landscape of CancerView all 38 articles
Integrated Multi-Omics Analysis Reveals Glycolytic Signature Predicts Pan-Cancer Immune Checkpoint Inhibitor Response and LDHA as a Combinatorial Target in Fumarate Hydratase-Deficient Renal Cell Carcinoma
Provisionally accepted
- 1Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
- 2Anhui University of Science and Technology, Huainan, China
- 3China Pharmaceutical University, Nanjing, China
- 4Shanghai Punan Hospital, Shanghai, China
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Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but aggressive renal malignancy associated with inactivation of the FH gene, resulting in poor prognosis and limited treatment options. Although immune checkpoint inhibitors (ICIs) have shown efficacy in various cancers, the response in FH-deficient RCC remains suboptimal, necessitating the identification of robust predictive biomarkers. This study highlights the metabolic remodeling in FH-deficient RCC, where the Warburg effect, characterized by elevated glycolysis, contributes to immune evasion and tumor progression. By integrating 41 single-cell RNA sequencing (scRNA-Seq) datasets across 19 malignancies, a glycolytic signature (Glyc.Sig) was developed, demonstrating a significant inverse correlation between glycolytic activity and ICI efficacy across multiple cancer types. Validation in pan-cancer immunotherapy cohorts revealed Glyc.Sig's superior predictive performance compared to conventional biomarkers. By screening Glyc.sig using CRISPR data, potential therapeutic targets for immune therapy synergy are identified. Mechanistically, LDHA was identified as a potential therapeutic target to enhance ICI response in FH-deficient RCC and other malignancies. Clinical validation via immunoblotting and immunohistochemistry in Renji Hospital cohorts further substantiated LDHA's potential as a combinatory target. This study underscores the importance of glycolytic reprogramming in cancer immunity and provides a dual diagnostic-predictive biomarker system for optimizing therapeutic strategies in FH-deficient RCC and other glycolytic tumors.
Keywords: FH-deficient RCC, immune checkpoint therapy, LdhA, Glycolysis, single-cell sequencing, Pan-cancer, Large data analysis
Received: 15 Jul 2025; Accepted: 28 Aug 2025.
Copyright: © 2025 Liu, Yuan, He, Zhou, Wang, Ye, Wang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jianfeng Wang, Shanghai Punan Hospital, Shanghai, China
Jin Zhang, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
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