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<p>Most patients with hepatocellular carcinoma (HCC) develop resistance to immune checkpoint blockade (ICB) or STING agonists despite their immune-stimulating activities. Here, we identify increased intratumoral B-cell infiltration as a mediator of acquired resistance. In HCC models with liver fibrosis in male mice, anti-PD-1 ICB or the STING agonist BMS-986301 increase intratumoral B-cell infiltration, circulating IL-10, and TIM-1<sup>+</sup> B-cells, promoting tertiary lymphoid structure formation. B-cell depletion combined with ICB or STING agonism improves survival, and STING agonism inhibits distant metastasis. In addition, co-targeting STING and TIM-1 enhances B-cell differentiation and antigen presentation, reduces intratumoral TIM-1<sup>+</sup> B-cells, and increases CD86 and MHC class II expression, thereby augmenting CD8<sup>+</sup> T-cell-mediated anti-tumor immunity. These findings reveal that B-cells contribute to ICB and STING therapy resistance in HCC, and that B-cell depletion or TIM-1 blockade can overcome acquired resistance to these immunotherapies.</p>

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Inhibiting B cells enhances the efficacy of STING agonism or immune checkpoint blockade in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Xin Liu,
  • Zelong Liu,
  • Chengzhan Zhu,
  • Tatsuya Kobayashi,
  • Pin-Ji Lei,
  • Yue Shi,
  • Dandan Yuan,
  • Jianguo Wang,
  • Min Li,
  • Aya Matsui,
  • Kassiana Mafra,
  • Tomofumi Ando,
  • Ken Kojo,
  • Rieke Schleinhege,
  • Kento Miyazaki,
  • Peigen Huang,
  • Ming Kuang,
  • Lloyd Bod,
  • Dan G. Duda

摘要

Most patients with hepatocellular carcinoma (HCC) develop resistance to immune checkpoint blockade (ICB) or STING agonists despite their immune-stimulating activities. Here, we identify increased intratumoral B-cell infiltration as a mediator of acquired resistance. In HCC models with liver fibrosis in male mice, anti-PD-1 ICB or the STING agonist BMS-986301 increase intratumoral B-cell infiltration, circulating IL-10, and TIM-1+ B-cells, promoting tertiary lymphoid structure formation. B-cell depletion combined with ICB or STING agonism improves survival, and STING agonism inhibits distant metastasis. In addition, co-targeting STING and TIM-1 enhances B-cell differentiation and antigen presentation, reduces intratumoral TIM-1+ B-cells, and increases CD86 and MHC class II expression, thereby augmenting CD8+ T-cell-mediated anti-tumor immunity. These findings reveal that B-cells contribute to ICB and STING therapy resistance in HCC, and that B-cell depletion or TIM-1 blockade can overcome acquired resistance to these immunotherapies.