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<p>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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年1月2日

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  • Qiuling Zhao,
  • Chenglong Li,
  • Mengsi Zhang,
  • Tingfang Gao,
  • Zhidong Wang,
  • Zhi Li,
  • Yan Qin,
  • Xinwen Xue,
  • Mengyun Chen,
  • Chengping Xu,
  • Guozhi Zhang,
  • Xiang Cui,
  • Kangjian Zhang,
  • Xiaowei Qi,
  • Xiu-Wu Bian,
  • Yi Yang

摘要

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.