Ionizing radiation (IR) can reprogram proteasome structure and function in cells and tissues. In this article, we show that IR can promote immunoproteasome synthesis with important implications for Ag processing and presentation and tumor immunity. Irradiation of a murine fibrosarcoma (FSA) induced dose-dependent de novo biosynthesis of the immunoproteasome subunits LMP7, LMP2, and Mecl-1, in concert with other changes in the Ag-presentation machinery (APM) essential for CD8+ T cell–mediated immunity, including enhanced expression of MHC class I (MHC-I), β2-microglobulin, transporters associated with Ag processing molecules, and their key transcriptional activator NOD-like receptor family CARD domain containing 5. In contrast, in another less immunogenic, murine fibrosarcoma (NFSA), LMP7 transcripts and expression of components of the immunoproteasome and the APM were muted after IR, which affected MHC-I expression and CD8+ T lymphocyte infiltration into NFSA tumors in vivo. Introduction of LMP7 into NFSA largely corrected these deficiencies, enhancing MHC-I expression and in vivo tumor immunogenicity. The immune adaptation in response to IR mirrored many aspects of the response to IFN-γ in coordinating the transcriptional MHC-I program, albeit with notable differences. Further investigations showed divergent upstream pathways in that, unlike IFN-γ, IR failed to activate STAT-1 in either FSA or NFSA cells while heavily relying on NF-κB activation. The IR-induced shift toward immunoproteasome production within a tumor indicates that proteasomal reprogramming is part of an integrated and dynamic tumor–host response that is specific to the stressor and the tumor and therefore is of clinical relevance for radiation oncology.

Exposure to ionizing radiation disrupts metabolic pathways and causes oxidative stress, which can lead to organ damage. In this study, urinary metabolites from mice exposed to high-dose and low-dose whole-body irradiation (WBI HDR, WBI LDR) or partial-body irradiation (PBI BM2.5) were analyzed using targeted and untargeted metabolomics approaches. Significant metabolic changes particularly in oxidative stress pathways were observed on Day 2 post-radiation. By Day 30, the WBI HDR group showed persistent metabolic dysregulation, while the WBI LDR and PBI BM2.5 groups were similar to control mice. Machine learning models identified metabolites that were predictive of the type of radiation exposure with high accuracy, highlighting their potential use as biomarkers for radiation damage and oxidative stress.