Abstract
Radiotherapy is a fundamental modality in cancer treatment, used in the management of more than half of cancer patients. Beyond direct cytotoxicity, ionizing radiation activates innate immune pathways and inflammatory cytokines required for local tumor control and systemic (abscopal) responses. Yet in human tumors, DNA damage-induced immune activation is attenuated compared with the robust responses observed in mice, suggesting a human-biased checkpoint that constrains radioimmunity. Here, we identify a tumor-intrinsic, human-biased farnesoid X receptor (FXR)-tripartite motif containing 22 (TRIM22)-STAT1 proteostatic checkpoint that suppresses radiation-induced type I interferon signaling. Ionizing radiation stabilizes FXR, a nuclear receptor, through ubiquitin-specific peptidase 7 (USP7)-dependent deubiquitination, enabling FXR to transcriptionally induce the E3 ligase TRIM22. TRIM22 selectively binds STAT1 and catalyzes its K48-linked ubiquitination and degradation, extinguishing interferon-stimulated gene (ISG) programs downstream of cGAS-STING signaling. This regulatory circuit is absent in murine tumor cells, which lack a TRIM22 family member capable of destabilizing STAT1, providing a mechanistic explanation for the stronger radiation-induced immune responses observed in mice. Genetic disruption of FXR or TRIM22 preserves STAT1, amplifies type I interferon signaling, and enhances CD8⁺ T-cell activation and abscopal tumor control in peripheral blood mononuclear cell-humanized mice. Pharmacologic modulation of this pathway with ursodeoxycholic acid, a bile acid used clinically with reported FXR-antagonistic activity, suppresses radiation-induced TRIM22, restores STAT1-ISG signaling, and potentiates radiotherapy alone or with anti-PD-1 without overt toxicity in humanized models. Collectively, these findings define a human-biased checkpoint that limits radiotherapy-induced immunity and is absent in murine tumor cells, and highlight the FXR-TRIM22-STAT1 axis as an actionable target to enhance cancer radioimmunotherapy.