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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\u2013PD-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 macrophages from both murine and human neuroblastoma expressed PD-L1. We identified cytokines, including macrophage migration inhibitory factor, secreted by the Mycn-nGEMM cancer cells that drive expression of PD-L1 on macrophages. Combining anti\u2013PD-L1 with CD40 agonist antibodies further improved survival in Mycn-nGEMM mice, demonstrating the potential for myeloid-targeting immunotherapies to overcome inhibitory barriers in immune-evasive neuroblastoma.<\/jats:p>","DOI":"10.1084\/jem.20231417","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T02:20:52Z","timestamp":1749608452000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Myeloid-targeting immunotherapies overcome inhibitory barriers in immune-evasive neuroblastoma"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1511-4361","authenticated-orcid":true,"given":"Marie","family":"M\u00e9nard","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California 1 Department of Neurology, , San Francisco, 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