Protein-based classification reveals an immune-hot subtype in IDH mutant astrocytoma with worse prognosis

Jihong Tang; Wenhua Fan; Yuyan Ruan; Xing Liu; Fufang Qiu; Jie Feng; Guoshi Huang; Mengli Yan; Hui Wang; Quanhua Mu; Ran Liu; Yingxi Yang; Zhi Huang; Yimeng Qiao; Xuejie Wang; Yumeng Guo; Mingchen Yu; Ying Zhang; Ruichao Chai; Fan Wu; Zheng Zhao; Zhaoshi Bao; Wei Hua; Kai Liu; Qianghu Wang; Ying Mao; Qing Chang; Tao Jiang; Jiguang Wang

doi:10.1016/j.ccell.2025.08.006

Protein-based classification reveals an immune-hot subtype in IDH mutant astrocytoma with worse prognosis

Cancer Cell. 2025 Nov 10;43(11):2136-2155.e14. doi: 10.1016/j.ccell.2025.08.006. Epub 2025 Sep 11.

Authors

Jihong Tang¹, Wenhua Fan², Yuyan Ruan¹, Xing Liu³, Fufang Qiu⁴, Jie Feng³, Guoshi Huang², Mengli Yan¹, Hui Wang¹, Quanhua Mu⁵, Ran Liu¹, Yingxi Yang¹, Zhi Huang¹, Yimeng Qiao¹, Xuejie Wang¹, Yumeng Guo¹, Mingchen Yu⁶, Ying Zhang³, Ruichao Chai³, Fan Wu³, Zheng Zhao³, Zhaoshi Bao², Wei Hua⁷, Kai Liu¹, Qianghu Wang⁸, Ying Mao⁷, Qing Chang³, Tao Jiang⁹, Jiguang Wang¹⁰

Affiliations

¹ Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Nervous System Disorders, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
² Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
³ Department of Molecular Neuropathology, Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
⁴ Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Nervous System Disorders, The Hong Kong University of Science and Technology, Hong Kong SAR, China; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University; National Center for Neruological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China.
⁵ Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Nervous System Disorders, The Hong Kong University of Science and Technology, Hong Kong SAR, China; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China.
⁶ Department of Pathophysiology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
⁷ Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University; National Center for Neruological Disorders, Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China.
⁸ Department of Bioinformatics, Institute for Brain Tumors, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China.
⁹ Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Department of Molecular Neuropathology, Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; Research Unit of Accurate Diagnosis, Treatment, and Translational Medicine of Brain Tumors, Chinese Academy of Medical Sciences, Beijing, China. Electronic address: taojiang1964@163.com.
¹⁰ Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Nervous System Disorders, The Hong Kong University of Science and Technology, Hong Kong SAR, China; SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen, China. Electronic address: jgwang@ust.hk.

PMID: 40939590
DOI: 10.1016/j.ccell.2025.08.006

Abstract

Intertumoral heterogeneity complicates treatment of IDH-mutant astrocytoma. We analyze spatiotemporal multi-omics data and discover four clusters: adipogenesis/fatty-acid-metabolism (AFM), proliferative/progenitor (PPR), immune/mesenchymal-enriched (IME), and neuronal (NEU). PPR and IME are associated with poorer prognosis, a result validated in The Cancer Genome Atlas (TCGA) and a Chinese cohort of 273 IDH-mutant astrocytomas. Longitudinal analysis of 189 initial-recurrent pairs shows an evolutionary shift toward PPR/IME subtypes. Mechanistically, PPR is enriched for CDKN2A/B deletions, whereas IME features increased gemistocytic differentiation (GD) and infiltration by exhausted T cells and plasma cells. Spatial multi-omics link GD morphology to mesenchymal-like (MES-like) tumor cell aggregates and lymphocyte-rich niches. MES-like tumor cells in IME overexpress interferon-stimulated genes such as GBP1, which we show promotes proliferation and migration. Finally, we develop an AI-powered classifier for patient stratification. Our work delineates protein-based clustering of IDH-mutant astrocytoma and reveals an immune-hot subgroup that may inform therapeutic development.

Keywords: GUIDE; IDH-mutant astrocytoma; gemistocytic differentiation; immune-hot glioma; lymphocytic infiltration; multi-omics; patient stratification; spatial proteomics; spatial transcriptomics; tumor heterogeneity.

MeSH terms

Astrocytoma* / genetics
Astrocytoma* / immunology
Astrocytoma* / pathology
Biomarkers, Tumor / genetics
Brain Neoplasms* / genetics
Brain Neoplasms* / immunology
Brain Neoplasms* / pathology
Humans
Isocitrate Dehydrogenase* / genetics
Mutation*
Prognosis

Substances

Isocitrate Dehydrogenase
IDH1 protein, human
Biomarkers, Tumor