ORIGINAL RESEARCH article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1638824

This article is part of the Research TopicNeural influences on tumor immunity: Exploring neuroimmunology in cancerView all 7 articles

A Multi-Cohort Validated OXPHOS Signature Predicts Survival and Immune Profiles in Grade II/III Glioma Patients

Provisionally accepted
Jun  MouJun Mou1Min  ZhangMin Zhang2Fumin  QinFumin Qin2Yajie  CuiYajie Cui2Keyou  XuKeyou Xu2Baoye  PangBaoye Pang2Xinyue  LiXinyue Li3Wanyi  TanWanyi Tan3Aiqi  YangAiqi Yang3Yaxin  LiuYaxin Liu3Lingjun  ShenLingjun Shen3Yanting  LiuYanting Liu2Kai  XuKai Xu2*
  • 1Sichuan University West China School of Medicine, Chengdu, China
  • 2Cancer Research Institute, Cancer Hospital, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
  • 3West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China

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

Grade II/III gliomas are invasive brain tumors with a high risk of malignant progression and significant clinical heterogeneity, underscoring the urgent need for reliable prognostic biomarkers to guide personalized treatment strategies. In this study, we developed a prognostic model based on mitochondrial oxidative phosphorylation (OXPHOS)-related gene signatures to investigate the molecular mechanisms driving glioma progression and to explore potential therapeutic targets. A total of 200 OXPHOS-related genes were analyzed in 512 grade II/III glioma samples from TCGA, and consensus clustering identified two distinct molecular subtypes (C1 and C2). The C2 subtype was associated with significantly poorer prognosis, higher immune scores, and enrichment in tumor-promoting pathways. Differentially expressed genes (DEGs) between subtypes were identified using the limma package, followed by ESTIMATE, MCPcounter, and CIBERSORT to assess the abundance or activity of immune cell populations within the TME, though not necessarily their anti-tumor function. Based on prognostic DEGs, we constructed a robust four-gene signature comprising MAOB, IGFBP2, SERPINA1, and LGR6, which demonstrated strong prognostic performance and stability across multiple independent validation cohorts. Furthermore, immunohistochemical (IHC) analysis of clinical glioma specimens confirmed elevated protein expression level of these four genes in tumor tissues. This OXPHOS-associated gene signature offers novel insights into the molecular classification, immune landscape, and prognosis of grade II/III gliomas, providing a promising foundation for precision oncology and targeted therapeutic interventions.

Keywords: grade II/III gliomas, Mitochondrial oxidative phosphorylation, Prognostic gene signature, riskscore model, immune microenvironment

Received: 31 May 2025; Accepted: 14 Jul 2025.

Copyright: © 2025 Mou, Zhang, Qin, Cui, Xu, Pang, Li, Tan, Yang, Liu, Shen, Liu and Xu. 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: Kai Xu, Cancer Research Institute, Cancer Hospital, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China

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