Targeting Necrotic Lipid Release In Tumors Enhances Immunosurveillance And Cancer Immunotherapy Of Glioblastoma 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 by 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 instant download after payment.

Tumors evolve to avoid immune destruction and establish an immunosuppressive microenvironment. Syngeneic mouse tumormodels are critical for understanding tumor immune evasion and testing cancer immunotherapy. Derived from established mousetumor cell lines that can already evade the immune system, these models cannot simulate early phases of immunoediting duringinitial tumorigenesis. We developed a syngeneic mouse teratoma model derived from noncancerous mouse embryonic stem cells1234567890();,:and conducted a genome-wide CRISPR screen to identify genes that impact early phases of cancer immunoediting. We found thatloss of pro-apoptotic tumor suppressor genes, including Trp53, increased necrosis in teratomas, releasing APOE lipid particles intothe extracellular milieu. Infiltrating T cells drawn to tumor necrotic regions accumulated lipids and became dysfunctional. Blockinglipid 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 tumorimmune interaction in human glioblastoma (GBM). Indeed, infiltrating T cells in TP53-mutated human GBM accumulated APOE andwere dysfunctional. Anti-APOE and anti-PDCD1 antibodies synergistically boosted anti-GBM immunity and prolonged survival inmice. Our results link mPTP-mediated tumor necrosis to immune evasion and suggest that targeting the uptake of lipids releasedby necrotic tumor cells by infiltrating immune cells can enhance cancer immunotherapy.Cell Research (2025) 0:1–17;