Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity

Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity

Abstract 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 (P...

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Main Authors: Yoichiro Narikawa, Atsuo Kuramasu, Masahiro Hosonuma, Masakazu Murayama, Eiji Funayama, Akiko Sasaki, Yuta Baba, Hitoshi Toyoda, Junya Isobe, Kohei Tajima, Rie Nakashima, Aya Sasaki, Yuki Maruyama, Yoshitaka Yamazaki, Midori Shida, Toshiaki Tsurui, Yuya Hirasawa, Hirotsugu Ariizumi, Tomoyuki Ishiguro, Risako Suzuki, Ryotaro Ohkuma, Yutaro Kubota, Takehiko Sambe, Mayumi Tsuji, Satoshi Wada, Atsushi Horiike, Shinichi Kobayashi, Takuya Tsunoda, Sei Kobayashi, Hitome Kobayashi, Tatsunori Oguchi, Toshikazu Shimane, Yuji Kiuchi, Kiyoshi Yoshimura
Format: Article
Language:English
Published: Springer 2025-08-01
Series:Cancer Immunology, Immunotherapy
Subjects:
Inosine
PD-1
CTLA-4
Immune checkpoint inhibitor
Tumor microenvironment
Online Access:https://doi.org/10.1007/s00262-025-04111-2
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Summary:Abstract 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.
ISSN:1432-0851

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