The UBA1-STUB1 Axis Mediates Cancer Immune Escape and Resistance to Checkpoint Blockade

Yi Bao; Gabriel Cruz; Yuping Zhang; Yuanyuan Qiao; Rahul Mannan; Jing Hu; Fan Yang; Mahnoor Gondal; Miriam Shahine; Sarah Kang; Somnath Mahapatra; Alec Chu; Jae Eun Choi; Jiali Yu; Heng Lin; Stephanie J Miner; Dan R Robinson; Yi-Mi Wu; Yang Zheng; Xuhong Cao; Fengyun Su; Rui Wang; Noshad Hosseini; Marcin Cieslik; Ilona Kryczek; Ulka Vaishampayan; Weiping Zou; Arul M Chinnaiyan

doi:10.1158/2159-8290.CD-24-0435

The UBA1-STUB1 Axis Mediates Cancer Immune Escape and Resistance to Checkpoint Blockade

Cancer Discov. 2025 Feb 7;15(2):363-381. doi: 10.1158/2159-8290.CD-24-0435.

Authors

Yi Bao^{1

2}, Gabriel Cruz^{1

2}, Yuping Zhang^{1

2}, Yuanyuan Qiao^{1

2

3}, Rahul Mannan^{1

2}, Jing Hu^{1

2

4}, Fan Yang^{1

2}, Mahnoor Gondal^{1

2

5}, Miriam Shahine¹, Sarah Kang¹, Somnath Mahapatra^{1

2}, Alec Chu^{1

2

5}, Jae Eun Choi^{1

2}, Jiali Yu^{6

7}, Heng Lin^{6

7}, Stephanie J Miner^{1

2}, Dan R Robinson^{1

2}, Yi-Mi Wu^{1

2}, Yang Zheng^{1

2}, Xuhong Cao^{1

2}, Fengyun Su^{1

2}, Rui Wang^{1

2}, Noshad Hosseini^{1

2}, Marcin Cieslik^{1

2

5}, Ilona Kryczek^{6

7}, Ulka Vaishampayan^{3

8}, Weiping Zou^{1

2

3

6

7}, Arul M Chinnaiyan^{1

2

3

9

10}

Affiliations

¹ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
² Department of Pathology, University of Michigan, Ann Arbor, Michigan.
³ Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.
⁴ Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁵ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
⁶ Department of Surgery, University of Michigan, Ann Arbor, Michigan.
⁷ Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, Michigan.
⁸ Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
⁹ Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan.
¹⁰ Department of Urology, University of Michigan, Ann Arbor, Michigan.

Abstract

Our study reveals UBA1 as a predictive biomarker for clinical outcomes in ICB cohorts, mediating cancer immune evasion and ICB resistance. We further highlight JAK1 stabilization as a key mechanism of UBA1 inhibition and nominate the UBA1-STUB1 axis as an immuno-oncology therapeutic target to improve the efficacy of ICB.

MeSH terms

Drug Resistance, Neoplasm*
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Neoplasms* / drug therapy
Neoplasms* / immunology
Neoplasms* / metabolism
Tumor Escape*
Ubiquitin-Activating Enzymes* / genetics
Ubiquitin-Activating Enzymes* / metabolism
Ubiquitin-Protein Ligases* / genetics
Ubiquitin-Protein Ligases* / metabolism

Substances

Ubiquitin-Activating Enzymes
Immune Checkpoint Inhibitors
UBA1 protein, human
Ubiquitin-Protein Ligases

Abstract

MeSH terms

Substances

Grants and funding