UBA2-High Osteosarcoma Suppresses Immune Infiltration by Autophagy-Mediated MHC-I Degradation.

Osteosarcoma responds poorly to immune-checkpoint blockade (ICB), and the molecular drivers of its immune-cold state remain unclear. Using multi-omics analyses, we identified an immune-cold osteosarcoma subtype characterized by enrichment of protein SUMOylation and found the SUMO E1 subunit UBA2 as a key driver. UBA2 was anomalously upregulated in osteosarcoma cohorts and linked to worse outcomes. Functionally, UBA2 promoted autophagy, thereby exerting noncanonical protumor and immunosuppressive effects. Mechanistically, UBA2 catalyzed SUMO2-dependent SUMOylation of SESN2, enhancing autophagic flux. At the immune interface, UBA2 did not alter the expression of immune checkpoint molecules but reduced surface MHC-I through NBR1-mediated autophagy-lysosomal degradation, thereby limiting CD8+ T-cell infiltration. In vivo, pharmacologic UBA2 inhibition with ML-792 slowed tumor growth and sensitized tumors to ICB therapy. Together, these findings show that UBA2 links SUMOylation to autophagy-driven loss of antigen presentation and immune exclusion, highlighting the UBA2-autophagy-MHC-I axis as a therapeutic target and potential biomarker in osteosarcoma.