Targeting necrotic lipid release in tumors enhances immunosurveillance and cancer immunotherapy of glioblastoma

IF 25.9 1区 生物学 Q1 CELL BIOLOGY
Yapeng Ji, Junyao Jiang, Lei Hu, Peng Lin, Mingshan Zhou, Song Hu, Minkai Wang, Yuchen Ji, Xianzhi Liu, Dongming Yan, Yang Guo, Adwait Amod Sathe, Bret M. Evers, Chao Xing, Xuelian Luo, Qi Xie, Weike Pei, Zhenyu Zhang, Hongtao Yu
{"title":"Targeting necrotic lipid release in tumors enhances immunosurveillance and cancer immunotherapy of glioblastoma","authors":"Yapeng Ji, Junyao Jiang, Lei Hu, Peng Lin, Mingshan Zhou, Song Hu, Minkai Wang, Yuchen Ji, Xianzhi Liu, Dongming Yan, Yang Guo, Adwait Amod Sathe, Bret M. Evers, Chao Xing, Xuelian Luo, Qi Xie, Weike Pei, Zhenyu Zhang, Hongtao Yu","doi":"10.1038/s41422-025-01155-y","DOIUrl":null,"url":null,"abstract":"<p>Tumors evolve to avoid immune destruction and establish an immunosuppressive microenvironment. Syngeneic mouse tumor models are critical for understanding tumor immune evasion and testing cancer immunotherapy. Derived from established mouse tumor cell lines that can already evade the immune system, these models cannot simulate early phases of immunoediting during initial tumorigenesis. We developed a syngeneic mouse teratoma model derived from noncancerous mouse embryonic stem cells and conducted a genome-wide CRISPR screen to identify genes that impact early phases of cancer immunoediting. We found that loss of pro-apoptotic tumor suppressor genes, including <i>Trp53</i>, increased necrosis in teratomas, releasing APOE lipid particles into the extracellular milieu. Infiltrating T cells drawn to tumor necrotic regions accumulated lipids and became dysfunctional. Blocking lipid uptake in T cells or reducing necrosis in teratomas by inactivating the mitochondrial permeability transition pore (mPTP) restored immunosurveillance. Because mouse teratomas were highly enriched for brain tissues, we next examined the tumor-immune interaction in human glioblastoma (GBM). Indeed, infiltrating T cells in TP53-mutated human GBM accumulated APOE and were dysfunctional. Anti-APOE and anti-PDCD1 antibodies synergistically boosted anti-GBM immunity and prolonged survival in mice. Our results link mPTP-mediated tumor necrosis to immune evasion and suggest that targeting the uptake of lipids released by necrotic tumor cells by infiltrating immune cells can enhance cancer immunotherapy.</p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"2 1","pages":""},"PeriodicalIF":25.9000,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41422-025-01155-y","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Tumors evolve to avoid immune destruction and establish an immunosuppressive microenvironment. Syngeneic mouse tumor models are critical for understanding tumor immune evasion and testing cancer immunotherapy. Derived from established mouse tumor cell lines that can already evade the immune system, these models cannot simulate early phases of immunoediting during initial tumorigenesis. We developed a syngeneic mouse teratoma model derived from noncancerous mouse embryonic stem cells and conducted a genome-wide CRISPR screen to identify genes that impact early phases of cancer immunoediting. We found that loss of pro-apoptotic tumor suppressor genes, including Trp53, increased necrosis in teratomas, releasing APOE lipid particles into the extracellular milieu. Infiltrating T cells drawn to tumor necrotic regions accumulated lipids and became dysfunctional. Blocking lipid uptake in T cells or reducing necrosis in teratomas by inactivating the mitochondrial permeability transition pore (mPTP) restored immunosurveillance. Because mouse teratomas were highly enriched for brain tissues, we next examined the tumor-immune interaction in human glioblastoma (GBM). Indeed, infiltrating T cells in TP53-mutated human GBM accumulated APOE and were dysfunctional. Anti-APOE and anti-PDCD1 antibodies synergistically boosted anti-GBM immunity and prolonged survival in mice. Our results link mPTP-mediated tumor necrosis to immune evasion and suggest that targeting the uptake of lipids released by necrotic tumor cells by infiltrating immune cells can enhance cancer immunotherapy.

Abstract Image

靶向肿瘤坏死脂质释放增强胶质母细胞瘤的免疫监测和肿瘤免疫治疗
肿瘤进化以避免免疫破坏并建立免疫抑制微环境。同基因小鼠肿瘤模型是了解肿瘤免疫逃避和测试癌症免疫治疗的关键。这些模型来源于已经建立的小鼠肿瘤细胞系,这些细胞系已经可以逃避免疫系统,因此不能模拟初始肿瘤发生过程中免疫编辑的早期阶段。我们开发了一种来自非癌小鼠胚胎干细胞的同基因小鼠畸胎瘤模型,并进行了全基因组CRISPR筛选,以确定影响癌症免疫编辑早期阶段的基因。我们发现,包括Trp53在内的促凋亡肿瘤抑制基因的缺失会增加畸胎瘤的坏死,将APOE脂质颗粒释放到细胞外环境中。浸润性T细胞被吸引到肿瘤坏死区域积聚脂质并变得功能失调。通过使线粒体通透性过渡孔(mPTP)失活,阻断T细胞脂质摄取或减少畸胎瘤坏死,可恢复免疫监视功能。由于小鼠畸胎瘤在脑组织中高度富集,我们接下来研究了人类胶质母细胞瘤(GBM)的肿瘤-免疫相互作用。事实上,tp53突变的人GBM中浸润的T细胞积累了APOE,并且功能失调。抗apoe和抗pdcd1抗体协同增强抗gbm免疫,延长小鼠生存期。我们的研究结果将mptp介导的肿瘤坏死与免疫逃避联系起来,并表明通过浸润免疫细胞靶向坏死肿瘤细胞释放的脂质摄取可以增强癌症免疫治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Cell Research
Cell Research 生物-细胞生物学
CiteScore
53.90
自引率
0.70%
发文量
2420
审稿时长
2.3 months
期刊介绍: Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信