西湖大学于洪涛团队近日取得一项新成果。经过不懈努力，他们研制了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。相关论文于2025年9月3日发表在《细胞研究》杂志上。

该课题组研究人员开发了一种来自非癌性胚胎干细胞的同基因同源畸胎瘤模型，并进行了全基因组CRISPR筛选，以鉴定影响癌症免疫编辑早期阶段的基因。该团队发现，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。

由于同主题畸胎瘤在脑组织中高度富集，研究人员接下来研究了人胶质母细胞瘤（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。他们的研究结果将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。

研究人员表示，肿瘤进化以避免免疫破坏并建立免疫抑制微环境。同基因肿瘤模型是了解肿瘤免疫逃避和检测肿瘤免疫治疗的关键。这些模型来源于已经建立的可以逃避免疫系统的无主题肿瘤细胞系，无法模拟初始肿瘤发生期间的免疫编辑的早期阶段。

附：英文原文

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

Author: Ji, Yapeng, Jiang, Junyao, Hu, Lei, Lin, Peng, Zhou, Mingshan, Hu, Song, Wang, Minkai, Ji, Yuchen, Liu, Xianzhi, Yan, Dongming, Guo, Yang, Sathe, Adwait Amod, Evers, Bret M., Xing, Chao, Luo, Xuelian, Xie, Qi, Pei, Weike, Zhang, Zhenyu, Yu, Hongtao

Issue&Volume: 2025-09-03

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.

DOI: 10.1038/s41422-025-01155-y

Source: https://www.nature.com/articles/s41422-025-01155-y