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

  • Cancer Immunol Res. 2026 Jul 2;14(7):1080-1099. doi: 10.1158/2326-6066.CIR-25-1321.
Lingfeng Yu  #  1  2 ,  Mengpan Li  #  1  2 ,  Tongtong Liu  #  1  2 ,  Jiangpeng Wu  #  1  2 ,  Huanliang Meng  2  3 ,  Wenyuan Xu  2  4 ,  Weisong Zhao  1  2 ,  Hao Zhu  5 ,  Zhen Wang  6 ,  Shibing Guo  7 ,  Zhuoying Wang  1  2 ,  Mengxiong Sun  1  2 ,  Tao Zhang  1  2 ,  Yafei Jiang  1  2 ,  Jing Han  1  2 ,  Xiaojun Ma  1  2 ,  Wei Sun  1  2 ,  Yingqi Hua  1  2 ,  Zhengdong Cai  1  2
Affiliations
  • 1. Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. Shanghai Bone Tumor Institution, Shanghai, China.
  • 3. Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
  • 4. Department of Orthopedics, Peking University First Hospital, Peking University, Beijing, China.
  • 5. Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 6. Senior Department of Orthopedics, The Fourth Medical Centre, Chinese PLA General Hospital, Beijing, China.
  • 7. Department of Musculoskeletal Oncology, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
  • # Contributed equally.
PMID: 42085301 DOI: 10.1158/2326-6066.CIR-25-1321
Abstract

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.

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