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ORIGINAL RESEARCH article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1664347

This article is part of the Research TopicNeural influences on tumor immunity: Exploring neuroimmunology in cancerView all 12 articles

Deciphering the Lactylation Landscape in Glioma: A Novel Gene Signature Predicts Patient Survival and Immunotherapy Sensitivity

Provisionally accepted
Xiaolong  TangXiaolong Tang1*Yi  LiuYi Liu2Congying  YangCongying Yang2Honglan  ZhangHonglan Zhang2Gongming  ZhangGongming Zhang2Qiao  WangQiao Wang2Sujie  JiangSujie Jiang2Xuzhu  GaoXuzhu Gao3Yongshuo  LiuYongshuo Liu4*Yanbin  DongYanbin Dong2*
  • 1Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
  • 2The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
  • 3The Second People's Hospital of Lianyungang, Lianyungang, China
  • 4Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

The final, formatted version of the article will be published soon.

Background: Glioma, the most prevalent primary brain tumor, takes advantage of lactylation, a metabolic modification linked to tumor behavior and clinical outcomes. Despite its significance, the role of lactylation in the pathogenesis and prognosis of glioma remains underexplored. This study established a lactylation-derived molecular signature to predict survival and response to immunotherapy in glioma. Methods: Leveraging the TCGA glioma cohort, we established a lactylation-related gene (LRG) signature via LASSO and Cox regression analyses, and its prognostic value was validated in independent cohorts. We comprehensively characterized the associations between the LRGs signature and clinicopathological features, tumor immunity (immune infiltration and response to immunotherapy), genomic instability (mutational burden and heterogeneity), tumor stemness, and therapeutic vulnerability. In vitro validation of the oncogenicity of HSPE1 was conducted using the CCK-8, colony formation, transwell, and apoptosis assays in U87 and U251 glioma cells. Results: A four-gene lactylation signature (KIF2C, CALD1, HSPE1, and IFI16) was identified. Elevated LRGs score were correlated with advanced tumor grade, poor prognosis, and reduced response to immunotherapy. Patients in the LRGs-high group exhibited adverse clinicopathological features, including advanced age, higher WHO grade, IDH wild-type status, and 1p/19q non-codeletion. The nomogram model based on the LRGs score exhibited robust prognostic accuracy (C-index = 0.860). LRGs-related genes were enriched in immune regulatory pathways, such as cytokine signaling and interferon-γ response pathways. The LRGs-high group displayed increased infiltration of immunosuppressive cells, such as M2 macrophages, MDSCs, and CAFs, and distinct genomic instability profiles. Crucially, HSPE1 knockdown significantly suppressed the proliferation and invasion of glioma cell lines. Conclusions: We defined a novel LRGs signature integrating metabolic and immune dysregulation in glioma. This signature served as an independent predictor of prognosis and immunotherapy. Furthermore, we identified HSPE1 as a critical driver of glioma progression.

Keywords: Glioma, lactylation, HSPE1, prognosis, Immunotherapy

Received: 11 Jul 2025; Accepted: 01 Sep 2025.

Copyright: © 2025 Tang, Liu, Yang, Zhang, Zhang, Wang, Jiang, Gao, Liu and Dong. 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:
Xiaolong Tang, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
Yongshuo Liu, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
Yanbin Dong, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China

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