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

Yapeng Ji^1,2,3 , Junyao Jiang⁴ , Lei Hu² , Peng Lin⁴ , Mingshan Zhou² , Song Hu² , Minkai Wang⁵ , Yuchen Ji⁵ , Xianzhi Liu⁵ , Dongming Yan⁵ , Yang Guo⁶ , Adwait Amod Sathe^7,8,9 , Bret M. Evers¹⁰ , Chao Xing^7,8,9 , Xuelian Luo^3,11 , Qi Xie⁴ , Weike Pei⁴ , Zhenyu Zhang^5,* , Hongtao Yu^1,2,3,*

¹Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China
²New Cornerstone Science Laboratory, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
³Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA
⁴School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
⁵Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
⁶Department of Neurosurgery, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
⁷Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
⁸Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA
⁹Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
¹⁰Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
¹¹Present address: School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
* Correspondence: Zhenyu Zhang(fcczhangzy1@zzu.edu.cn)Hongtao Yu(yuhongtao@westlake.edu.cn)

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.

https://doi.org/10.1038/s41422-025-01155-y

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