Wiley Acta Medica Okayama 1347-9032 115 10 2024 Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron immunotherapy (B-NIT) 3231 3247 EN Takuya Fujimoto Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Osamu Yamasaki Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Noriyuki Kanehira Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hirokazu Matsushita Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute Yoshinori Sakurai Institute for Integrated Radiation and Nuclear Science, Kyoto University Naoya Kenmotsu Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Ryo Mizuta Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Natsuko Kondo Institute for Integrated Radiation and Nuclear Science, Kyoto University Takushi Takata Institute for Integrated Radiation and Nuclear Science, Kyoto University Mizuki Kitamatsu Faculty of Science and Engineering, Kindai University Kazuyo Igawa Neutron Therapy Research Center, Okayama University Atsushi Fujimura Neutron Therapy Research Center, Okayama University Yoshihiro Otani Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Makoto Shirakawa Neutron Therapy Research Center, Okayama University Kunitoshi Shigeyasu Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Fuminori Teraishi Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yosuke Togashi Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Minoru Suzuki Institute for Integrated Radiation and Nuclear Science, Kyoto University Toshiyoshi Fujiwara Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiroyuki Michiue Neutron Therapy Research Center, Okayama University Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8(+) T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44(+) effector memory T cells and CD69(+) early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers. No potential conflict of interest relevant to this article was reported.