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<p>Protein kinases contribute to hepatocellular carcinoma (HCC) development and immune evasion, posing major challenges for HCC management. Here we show STE20/SPS1-related proline/alanine-rich kinase (SPAK) as a candidate immune exhaustion–associated gene identified through a pooled screen of protein kinases. By integrating bioinformatic analyses, data from patient cohorts, and functional studies in mouse models and cell lines, we demonstrate that elevated expression of SPAK promotes HCC progression, enhances stemness, drives immune exhaustion, and contributes to resistance to targeted therapies. Mechanistically, SPAK phosphorylates GSK3β at Ser9, thereby inhibiting proteasome-mediated degradation of c-Jun and PD-L1. Additionally, we find that DNMT3B-dependent intragenic methylation of <i>SPAK</i> contributes to its high expression in HCC. Notably, the SPAK inhibitor exhibits potent inhibitory effects and synergizes with PD-1 blockade to enhance antitumor efficacy. In summary, these findings establish SPAK as a driver of oncogenesis and immune exhaustion in HCC and highlight dual inhibition as a potential therapeutic strategy.</p>

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Targeting SPAK suppresses progression and averts an immune exhaustive microenvironment in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月12日

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  • Yonglong Pan,
  • Chenglong Zeng,
  • Yi He,
  • Ruizhi Chang,
  • Jingjing Wu,
  • Chaoyi Yuan,
  • Haisen Li,
  • Chen Su,
  • Mengzhen Han,
  • Pengcheng Li,
  • Xinxin Li,
  • Hongwei Zhang,
  • Furong Liu,
  • Huifang Liang,
  • Zifu Li,
  • Mi Wu,
  • Limin Xia,
  • Jianfeng Liu,
  • Xiaoping Chen,
  • Wanguang Zhang,
  • Bixiang Zhang,
  • Ze-yang Ding

摘要

Protein kinases contribute to hepatocellular carcinoma (HCC) development and immune evasion, posing major challenges for HCC management. Here we show STE20/SPS1-related proline/alanine-rich kinase (SPAK) as a candidate immune exhaustion–associated gene identified through a pooled screen of protein kinases. By integrating bioinformatic analyses, data from patient cohorts, and functional studies in mouse models and cell lines, we demonstrate that elevated expression of SPAK promotes HCC progression, enhances stemness, drives immune exhaustion, and contributes to resistance to targeted therapies. Mechanistically, SPAK phosphorylates GSK3β at Ser9, thereby inhibiting proteasome-mediated degradation of c-Jun and PD-L1. Additionally, we find that DNMT3B-dependent intragenic methylation of SPAK contributes to its high expression in HCC. Notably, the SPAK inhibitor exhibits potent inhibitory effects and synergizes with PD-1 blockade to enhance antitumor efficacy. In summary, these findings establish SPAK as a driver of oncogenesis and immune exhaustion in HCC and highlight dual inhibition as a potential therapeutic strategy.