Volume 36, No 1, Jan 2026

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 36 Issue 1, January 2026: 38-50

ORIGINAL ARTICLES

Tumor PD-L1 induces β2m ubiquitylation and degradation for cancer cell immune evasion

Qiuling Zhao^1,† , Chenglong Li^1,† , Mengsi Zhang^1,† , Tingfang Gao^1,2,† , Zhidong Wang^1,2 , Zhi Li¹ , Yan Qin¹ , Xinwen Xue¹ , Mengyun Chen² , Chengping Xu¹ , Guozhi Zhang³ , Xiang Cui³ , Kangjian Zhang^4,5 , Xiaowei Qi^3,* , Xiu-Wu Bian^1,* , Yi Yang^1,2,*

¹Institute of Pathology & Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing, China
²Chongqing Institute of Advanced Pathology, Jinfeng Laboratory, Chongqing, China
³Department of Breast and Thyroid Surgery, Southwest Hospital of Third Military Medical University (Army Medical University), Chongqing, China
⁴Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China
⁵Academician Expert Workstation of Fengxian District, Shanghai Yuansong Biotechnology Limited Company, Shanghai, China
^†These authors contributed equally: Qiuling Zhao, Chenglong Li, Mengsi Zhang, Tingfang Gao
Correspondence: Xiaowei Qi(qxw9908@tmmu.edu.cn)Xiu-Wu Bian(bianxiuwu@tmmu.edu.cn)Yi Yang(yiyang-09@tmmu.edu.cn)

Resistance to anti-PD-1/PD-L1 immune checkpoint blockade continues to be a critical challenge undermining its therapeutic efficacy in clinical applications. Most of the resistance mechanisms characterized to date have predominantly involved external factors beyond PD-L1. Here, we unexpectedly discovered that PD-L1 itself possesses E3 ubiquitin ligase activity to induce β2m ubiquitylation and subsequent degradation, which notably reduces MHC-I levels on the surface of tumor cells and antigen-presenting cells, thereby contributing to tumor cell evasion of recognition by CD8+ T cells and ultimately resulting in resistance to anti-PD-1/PD-L1 immunotherapy, particularly in tumors with low basal β2m expression. Disrupting the E3 ubiquitin ligase activity of PD-L1 or interfering with the PD-L1–β2m interaction dramatically enhanced the sensitivity of tumor cells to PD-L1 blockade therapy. Our study reveals a previously unknown function of PD-L1 in the immune evasion of tumor cells, expanding our understanding of intrinsic resistance mechanisms to immune checkpoint blockade therapy.

https://doi.org/10.1038/s41422-025-01205-5

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