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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2025-08-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04111-2 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yoichiro Narikawa |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6f69f88587fd4d89aeba5ab31aa12d4d |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-6f69f88587fd4d89aeba5ab31aa12d4d2025-08-24T11:32:28ZengSpringerCancer Immunology, Immunotherapy1432-08512025-08-0174911210.1007/s00262-025-04111-2Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunityYoichiro Narikawa0Atsuo Kuramasu1Masahiro Hosonuma2Masakazu Murayama3Eiji Funayama4Akiko Sasaki5Yuta Baba6Hitoshi Toyoda7Junya Isobe8Kohei Tajima9Rie Nakashima10Aya Sasaki11Yuki Maruyama12Yoshitaka Yamazaki13Midori Shida14Toshiaki Tsurui15Yuya Hirasawa16Hirotsugu Ariizumi17Tomoyuki Ishiguro18Risako Suzuki19Ryotaro Ohkuma20Yutaro Kubota21Takehiko Sambe22Mayumi Tsuji23Satoshi Wada24Atsushi Horiike25Shinichi Kobayashi26Takuya Tsunoda27Sei Kobayashi28Hitome Kobayashi29Tatsunori Oguchi30Toshikazu Shimane31Yuji Kiuchi32Kiyoshi Yoshimura33Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDivision of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of MedicineDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDepartment of Hospital Pharmaceutics, School of Pharmacy, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityPharmacological Research Center, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDivision of Medical Oncology, Department of Medicine, Showa Medical University School of MedicineDivision of Medical Oncology, Department of Medicine, Showa Medical University School of MedicineDivision of Medical Oncology, Department of Medicine, Showa Medical University School of MedicineDivision of Medical Oncology, Department of Medicine, Showa Medical University School of MedicineDivision of Medical Oncology, Department of Medicine, Showa Medical University School of MedicineDivision of Medical Oncology, Department of Medicine, Showa Medical University School of MedicineDivision of Clinical Pharmacology, Department of Pharmacology, Showa Medical University School of MedicinePharmacological Research Center, Showa Medical UniversityDepartment of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDivision of Medical Oncology, Department of Medicine, Showa Medical University School of MedicineClinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityDivision of Medical Oncology, Department of Medicine, Showa Medical University School of MedicineDepartment of Otorhinolaryngology, Showa Medical University Fujigaoka HospitalDepartment of Otorhinolaryngology-Head and Neck Surgery, Showa Medical University School of MedicineDivision of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of MedicineHead and Neck Oncology Center, Showa Medical UniversityDivision of Medical Pharmacology, Department of Pharmacology, Showa Medical University School of MedicineDepartment of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa Medical UniversityAbstract 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.https://doi.org/10.1007/s00262-025-04111-2InosinePD-1CTLA-4Immune checkpoint inhibitorTumor microenvironment |
| spellingShingle | 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 Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity Cancer Immunology, Immunotherapy Inosine PD-1 CTLA-4 Immune checkpoint inhibitor Tumor microenvironment |
| title | Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity |
| title_full | Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity |
| title_fullStr | Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity |
| title_full_unstemmed | Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity |
| title_short | Inosine shapes PD-1 blockade responses and synergizes with dual PD-1/CTLA-4 immunotherapy to enhance antitumor immunity |
| title_sort | inosine shapes pd 1 blockade responses and synergizes with dual pd 1 ctla 4 immunotherapy to enhance antitumor immunity |
| topic | Inosine PD-1 CTLA-4 Immune checkpoint inhibitor Tumor microenvironment |
| url | https://doi.org/10.1007/s00262-025-04111-2 |
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