Inhibiting B cells enhances the efficacy of STING agonism or immune checkpoint blockade in hepatocellular carcinoma
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.
Authors
- Chengzhan Zhu (ORCID: https://orcid.org/0000-0002-2775-5863)
- Peigen Huang (ORCID: https://orcid.org/0000-0002-3184-6493)
- Dan G. Duda (ORCID: https://orcid.org/0000-0001-7065-8797)
- Ken Kojo (ORCID: https://orcid.org/0000-0001-8744-8358)
- Ming Kuang (ORCID: https://orcid.org/0000-0002-7397-5779)
- Kento Miyazaki
- Yue Shi (ORCID: https://orcid.org/0000-0002-2860-2666)
- Xin Liu (ORCID: https://orcid.org/0000-0002-7529-3149)
- Pin‐Ji Lei (ORCID: https://orcid.org/0000-0003-2539-5179)
- Tatsuya Kobayashi (ORCID: https://orcid.org/0000-0002-3889-5765)
- Dandan Yuan (ORCID: https://orcid.org/0000-0001-7858-3777)
- Zelong Liu (ORCID: https://orcid.org/0000-0002-3583-1731)
- Tomofumi Ando (ORCID: https://orcid.org/0000-0001-5327-3297)
- Aya Matsui (ORCID: https://orcid.org/0000-0002-4903-3511)
- Jianguo Wang (ORCID: https://orcid.org/0000-0002-8030-2900)
- Min Li (ORCID: https://orcid.org/0000-0003-1350-9909)
- Lloyd Bod (ORCID: https://orcid.org/0000-0001-8124-0863)
- Kassiana Mafra
- Rieke Schleinhege
Institutions
- Kanazawa University (JP)
- Broad Institute (US)
- Qingdao University (CN)
- Houston Methodist (US)
- Harvard University (US)
- Sun Yat-sen University (CN)
- Anhui Medical University (CN)
- Massachusetts General Hospital (US)
- Shandong Tumor Hospital (CN)
- Affiliated Hospital of Qingdao University (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Zhejiang Provincial People's Hospital (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Center for Cancer Research (US)
- Shandong First Medical University (CN)
- Hangzhou Medical College (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-08
- DOI
- https://doi.org/10.1038/s41467-025-66581-3
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- U.S. Department of Defense
- Cancer Research Institute
- Bristol-Myers Squibb
- Massachusetts General Hospital
- Lung Cancer Research Foundation
- National Institutes of Health
- DOD Peer Reviewed Cancer Research Program