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<p>While immune checkpoint inhibitors targeting programmed cell death-ligand 1 (PD-L1) demonstrate clinical efficacy in hepatocellular carcinoma (HCC), tumor cells frequently evade immune surveillance through PD-L1 overexpression, a phenomenon whose regulatory mechanisms remain poorly understood. Through integrated analysis of single-cell transcription sequence data, we identified aberrant upregulation of Lamin B2 (LMNB2) specifically in immunotherapy-sensitive HCC patients. Functional characterization revealed that LMNB2 acts as a transcriptional regulator of PD-L1, potentiating immune escape mechanisms in HCC cells during co-culture with Jurkat cells. Notably, we discovered that speckle-type POZ protein (SPOP) directly interacts with LMNB2 to mediate its ubiquitination and proteasomal degradation, thereby maintaining physiological PD-L1 expression levels. Clinically relevant <i>SPOP</i> mutations or reduced SPOP expression impaired this regulatory mechanism, leading to LMNB2 accumulation and subsequent PD-L1 hyperactivation. Importantly, combinatorial targeting of LMNB2 with Atezolizumab (PD-L1 inhibitor) displayed a synergistic effect on suppressing tumor progression both in vitro and in vivo, particularly in HCC models with <i>SPOP</i> mutations or LMNB2 overexpression. These findings unveil a novel ubiquitination-dependent regulatory axis in HCC immune evasion and propose targeted co-inhibition strategies to overcome HCC immunotherapy resistance.</p>

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LMNB2-mediated high PD-L1 transcription triggers the immune escape of hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月7日

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  • Yuxuan Li,
  • Jie Zhu,
  • Fengguang Zhai,
  • Yidong Ge,
  • Ziqing Zhan,
  • Shuyan Wang,
  • Lili Kong,
  • Jianan Zhao,
  • Lecheng Hu,
  • Siyuan Wang,
  • Jiaxin Shi,
  • Jianing Mao,
  • Zongdong Yu,
  • Haoyun Wang,
  • Jiabei Jin,
  • Mengxiang Zhao,
  • Hong Li,
  • Xiaofeng Jin

摘要

While immune checkpoint inhibitors targeting programmed cell death-ligand 1 (PD-L1) demonstrate clinical efficacy in hepatocellular carcinoma (HCC), tumor cells frequently evade immune surveillance through PD-L1 overexpression, a phenomenon whose regulatory mechanisms remain poorly understood. Through integrated analysis of single-cell transcription sequence data, we identified aberrant upregulation of Lamin B2 (LMNB2) specifically in immunotherapy-sensitive HCC patients. Functional characterization revealed that LMNB2 acts as a transcriptional regulator of PD-L1, potentiating immune escape mechanisms in HCC cells during co-culture with Jurkat cells. Notably, we discovered that speckle-type POZ protein (SPOP) directly interacts with LMNB2 to mediate its ubiquitination and proteasomal degradation, thereby maintaining physiological PD-L1 expression levels. Clinically relevant SPOP mutations or reduced SPOP expression impaired this regulatory mechanism, leading to LMNB2 accumulation and subsequent PD-L1 hyperactivation. Importantly, combinatorial targeting of LMNB2 with Atezolizumab (PD-L1 inhibitor) displayed a synergistic effect on suppressing tumor progression both in vitro and in vivo, particularly in HCC models with SPOP mutations or LMNB2 overexpression. These findings unveil a novel ubiquitination-dependent regulatory axis in HCC immune evasion and propose targeted co-inhibition strategies to overcome HCC immunotherapy resistance.