Abstract Background: Immunotherapies have greatly expanded the therapeutic options available to cancer patients with treatment-refractory solid tumors. However, patients who fail frontline hormone therapy and develop castration-resistant prostate cancer (CRPC) remain unresponsive to immune checkpoint blockade (ICB). This is in part due to the immunologically “cold” prostate landscape that lacks T cells that can respond to ICB and mediate anti-tumor immunity. As many as 30% of CRPC patients develop an aggressive form of small cell or neuroendocrine prostate cancer (NEPC) that is highly metastatic and has no effective standard treatment options. Paradoxically, it was recently shown that NEPC tumors can harbor a more “inflamed” tumor microenvironment (TME) despite having poorer overall survival compared with other prostate cancer subtypes. Interferon gamma (IFNg) signaling that can increase antigen presentation and anti-tumor immunity associated with ICB response was identified as a driver of this signature in NEPC. Thus, understanding the mechanisms by which IFNg contributes to NEPC development and immune responses may lead to new immunotherapy strategies for NEPC patients. Methods: To functionally dissect tumor-immune interactions in NEPC in situ, we have recently developed a novel mouse model of NEPC. Using our electroporation-based genetically engineered mouse models (EPO-GEMMs) that allow us to generate prostate tumors with any genetic background (Murphy and Ruscetti 2022), we used CRISPR/Cas9 vectors targeting three tumor suppressor genes commonly lost in human NEPC, Pten, p53, and Rb1 (PtPRb), to generate NEPC tumors in mice in a matter of months. Results: PtPRb tumors harbored higher immune infiltrates, IFNg signaling, and antigen presentation levels compared to non-NEPC EPO-GEMMs we previously developed (Murphy et al. Can Res 2025). Despite their inflamed phenotype, treatment of PtPRb tumors with PD-1 blocking antibody ICB led to strikingly decreased overall survival and disease hyper-progression compared to IgG-treated controls. IFNg was found to be upregulated in PtPRb NEPC tumor cells compared to non-NEPC and to induce tumor intrinsic growth signaling. Moreover, treatment with inhibitors of NFkB, activated downstream of IFNg, could directly block NEPC growth in vitro and PtPRb tumors grown in NSG mice displayed less neuroendocrine lineage markers than those in wildtype tumor-bearing mice. Macrophages, which can respond to IFNg in the TME and promote ICB resistance, were also prevalent in NEPC tumors and polarized into a hyper-inflammatory state. Subsequent antibody blockade of the IFNg receptor could reduce macrophage numbers and inflammatory polarization and increase overall survival in PtPRb tumor-bearing mice. Conclusions 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr PR003.
Murphy et al. (Tue,) studied this question.