Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity
Inosine, a bacterial metabolite and agonist of the adenosine A2A receptor, modulates antitumor immunity. However, its precise effects on immune checkpoint inhibitors remain unclear. This study aimed to evaluate the impact of inosine on the efficacy of anti-programmed cell death protein 1 (PD-1) therapy and explore strategies to counteract any potential inhibitory effects. In in vitro co-culture systems, inosine selectively suppressed cancer cell growth without impairing T-cell viability. In a murine subcutaneous tumor model, inosine treatment reduced tumor growth and was associated with elevated interferon-gamma levels in the tumor microenvironment, along with increased infiltration by tumor-infiltrating lymphocytes and enhanced splenic CD4⁺ and CD8⁺ T-cell frequencies. However, the combination of inosine with anti-PD-1 therapy attenuated the antitumor effect and increased cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in splenic T cells compared to levels after anti-PD-1 monotherapy. To overcome this inhibitory effect, we tested whether adding an anti-CTLA-4 antibody could restore antitumor immunity. Notably, the combination of inosine with both anti-PD-1 and anti-CTLA-4 antibodies significantly enhanced antitumor efficacy. These findings suggest that inosine may synergize with dual ICI therapy and represent a promising adjunct to improve immunotherapeutic outcomes.
Authors
- Takehiko Sambe (ORCID: https://orcid.org/0000-0001-6730-7873)
- Toshiaki Tsurui (ORCID: https://orcid.org/0000-0002-6167-8953)
- Eiji Funayama
- Aya Sasaki
- Yutaro Kubota (ORCID: https://orcid.org/0000-0002-2917-8764)
- Kiyoshi Yoshimura (ORCID: https://orcid.org/0000-0003-4816-1826)
- Atsuo Kuramasu
- Midori Shida
- Yuta Baba (ORCID: https://orcid.org/0000-0002-5743-0306)
- Hirotsugu Ariizumi (ORCID: https://orcid.org/0000-0003-1663-8730)
- Ryotaro Ohkuma (ORCID: https://orcid.org/0000-0003-4121-2491)
- Toshikazu Shimane (ORCID: https://orcid.org/0000-0002-0816-0223)
- Atsushi Horiike (ORCID: https://orcid.org/0000-0002-1632-3125)
- Masakazu Murayama
- Yoichiro Narikawa
- Mayumi Tsuji (ORCID: https://orcid.org/0000-0001-8005-9069)
- Hitoshi Toyoda
- Shinichi Kobayashi (ORCID: https://orcid.org/0000-0002-1321-3908)
- Junya Isobe
- Tomoyuki Ishiguro
- Satoshi Wada (ORCID: https://orcid.org/0000-0001-6528-5914)
- Yuki Maruyama (ORCID: https://orcid.org/0000-0003-2695-1472)
- Yuji Kiuchi (ORCID: https://orcid.org/0000-0001-7198-3735)
- Rie Nakashima (ORCID: https://orcid.org/0000-0001-9193-1799)
- Masahiro Hosonuma (ORCID: https://orcid.org/0000-0002-5861-7543)
- Hitome Kobayashi (ORCID: https://orcid.org/0000-0002-4057-4514)
- Yuya Hirasawa
- Akiko Sasaki (ORCID: https://orcid.org/0000-0003-4219-554X)
- Tatsunori Oguchi
- Sei Kobayashi
- Kohei Tajima
- Risako Suzuki
- Takuya Tsunoda
- Yoshitaka Yamazaki
Institutions
- SHOWA Medical University (JP)
- Therapeutics Clinical Research (US)
- SHOWA Medical University Fujigaoka Hospital (JP)
- SHOWA Medical University Hospital (JP)
- Showa Pharmaceutical University (JP)
Publication Details
- Journal
- Cancer Immunology Immunotherapy
- Published
- 2025-08-19
- DOI
- https://doi.org/10.1007/s00262-025-04111-2
- Citations
- 4
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- Japan Society for the Promotion of Science