biostudies-literatureMenard MAlex's Lemonade Stand FoundationCancer Research UKNational Cancer CenterUehara Memorial FoundationNational Institutes of HealthAlex’s Lemonade Stand FoundationU.S. Department of DefenseSt. Baldrick's FoundationNCI NIH HHSNINDS NIH HHSEfim Guzik chairSt. Baldrick’s FoundationNIH HHSe20231417https://www.ebi.ac.uk/biostudies/studies/S-EPMC12263170biostudies-literatureUnknown222(9)Neuroblastomas are highly heterogeneous tumors originating from neural crest-derived cells destined to form the sympathetic nervous system. Nearly half of high-risk tumors present with amplification of the MYCN proto-oncogene. Here, we describe a Mycn-driven, transplantable, non-germline, genetically engineered mouse model (Mycn-nGEMM). Mycn-nGEMM tumors recapitulate the immune-evasive, macrophage-rich tumor microenvironment of high-risk, MYCN-amplified human neuroblastoma. Treatment of tumor-bearing mice with anti-PD-L1, but not anti-PD-1 or anti-CTLA-4, inhibited tumor growth, profoundly remodeling the tumor microenvironment by depleting anti-inflammatory macrophages and increasing T cell infiltration. Surprisingly, while tumor cells showed low expression of PD-L1, anti-inflammatory macrThe Journal of experimental medicineMyeloid-targeting immunotherapies overcome inhibitory barriers in immune-evasive neuroblastoma.PMC12263170U01CA217864CA170257P1P30 CA082103P01 CA217959P30CA82103R01 NS125668U01 CA217864R01NS125668P01CA217959Maris JMAsgharzadeh SLopez VGrossmann LDNasholm NMcHenry LGustafson WCFarrel AWang LBarata MJYoda HLu EDShimada HKaufman RFernandez GEWong-Michalak SMenard MSimonds EFKennedy RJWeiss WAfalseMyeloid-targeting immunotherapies overcome inhibitory barriers in immune-evasive neuroblastoma.Neuroblastomas are highly heterogeneous tumors originating from neural crest-derived cells destined to form the sympathetic nervous system. Nearly half of high-risk tumors present with amplification of the MYCN proto-oncogene. Here, we describe a Mycn-driven, transplantable, non-germline, genetically engineered mouse model (Mycn-nGEMM). Mycn-nGEMM tumors recapitulate the immune-evasive, macrophage-rich tumor microenvironment of high-risk, MYCN-amplified human neuroblastoma. Treatment of tumor-bearing mice with anti-PD-L1, but not anti-PD-1 or anti-CTLA-4, inhibited tumor growth, profoundly remodeling the tumor microenvironment by depleting anti-inflammatory macrophages and increasing T cell infiltration. Surprisingly, while tumor cells showed low expression of PD-L1, anti-inflammatory macr2025-01-01T00:00:00Z2025 Sep2026-07-16T23:39:52.891Z2026-07-12T03:11:45.947ZS-EPMC122631704065810510.1084/jem.20231417