Abstract PR-02: Loss of tumor-intrinsic type I IFN facilitates and predicts bone-metastatic progression in advanced prostate cancer and drives radiotherapeutic resistance

Abstract Background: Bone metastases occur in up to 90% of men with castration-resistant prostate cancer (CRPC) and are invariably fatal. A "cold" tumor microenvironment has been implicated in the failure of conventional and targeted therapies to improve long-term survival in metastatic disease. Yet, studies interrogating the bone metastatic niche for candidate drivers of therapeutic resistance are lacking, as are real-world strategies to advance precision approaches that reduce patient mortality. Here we define explicit and previously undisclosed features of the tumor-immune landscape that shape CRPC progression to bone and reveal key predictors of resistance to radioligand therapy (RLT). Methods: We performed in-depth single cell and digital spatial profiling linked to transcriptomic analysis of >230 prostate cancer patients from 6 independent cohorts spanning >100 tissues and PDX from adenocarcinomas (non-metastatic and metastatic) to lymph node (LN) and bone metastases, with >32 matched tumors. Results: Bone metastases show a significant site-specific loss of type I interferon (IFN-I) signaling and antigen presentation markers (HLA-I) compared to LN and primary tumors. Tumor-intrinsic (TI) IFN-I signaling is predictive of bone metastasis (HR=0.92, p=0.04) while tumor cell HLA-I is predictive of bone metastasis-free survival (HR=0.97, p=0.03) and biochemical recurrence (HR=0.97, p=0.009). Bone metastasis is correlated with robust suppression of both TI IFN-I signaling and HLA-I (r=0.79, p<0.0001) compared to metastatic and non-metastatic primaries. Metastasis is associated with increased Treg, while tumor-excluded memory T cells are only predictive of better bone metastasis-free survival when active TI IFN-I is intact. A bone-specific enrichment of tumor-infiltrating M2 macrophages is observed yet is not prognostic. Similarly, a bone-specific loss of HLA-II and dendritic cell activation is evidenced yet holds no predictive value. Notably, we identified a bone-specific loss of >15 IFN-I regulated druggable targets compared to matched adenocarcinomas concurrent to a bone-specific TI increase in B7-H3, validated in PDX and 3 independent cohorts. Systemic immune analysis in men receiving PSMA-targeted RLT reveal that radiographic progression in CRPC can be predicted by IFN-I driven antigen presentation markers in novel immune subsets as early as cycle 2 of treatment. Conclusion: We reveal the first in-depth profiling of the bone metastatic landscape in CRPC and identify TI IFN-I biomarkers as superior to the quantitation and characterization of tumor infiltrating immune cells to predict risk of bone metastasis. Our findings suggest the loss of tumor immunogenicity in CRPC is a critical mediator of bone-specific progression, drives therapeutic resistance and underpins response to targeted RLT. Here, we highlight the utility of TI IFN-I markers to predict CRPC progression to bone and discuss novel points of intervention to limit autoimmune responses to RLT and IFN-activating therapies that may improve survival for men with a lethal stage of disease. Citation Format: Katie L. Owen, Linden J. Gearing, Chris Hovens, Shahneen Sandhu, Michael Hofman, Belinda S. Parker, Luc Furic. Loss of tumor-intrinsic type I IFN facilitates and predicts bone-metastatic progression in advanced prostate cancer and drives radiotherapeutic resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr PR-02.