Jung Min Shin, Chan-Hyeong Lee, Soyoung Son, Chan Ho Kim, Jae Ah Lee, Hyewon Ko, Sol Shin, Seok Ho Song, Seong-Sik Park, Ju-Hyun Bae, Ju-Mi Park, Eun-Ji Choe, Moon-Chang Baek,^* and Jae Hyung Park^*

J. M. Shin, S. Son, C. H. Kim, J. A. Lee, S. H. Song, J. H. Park
School of Chemical Engineering College of Engineering Sungkyunkwan University 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea

J. M. Shin
Department of Genetic Resources National Marine Biodiversity Institute of Korea (MABIK) 75 Jangsan-ro 101-gil, Janghang-eup, Seocheon 33662, Republic of Korea

C.-H. Lee, S.-S. Park, J.-H. Bae, J.-M. Park, E.-J. Choe, M.-C. Baek
Department of Molecular Medicine CMRI Exosome Convergence Research Center (ECRC) School of Medicine Kyungpook National University Daegu 41944, Republic of Korea

S. Son, S. Shin, J. H. Park
Department of Health Sciences and Technology SAIHST Sungkyunkwan University 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea

H. Ko
Bionanotechnology Research Center Korea Research Institute of Bioscience & Biotechnology 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea

J. H. Park
Biomedical Institute for Convergence at SKKU (BICS) Sungkyunkwan University 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea

J.M.S. and C.H.L. contributed equally to this work.

^*Corresponding author.

Despite their potent antitumor activity, clinical application of immune checkpoint inhibitors has been significantly limited by their poor response rates (<30%) in cancer patients, primarily due to immunosuppressive tumor microenvironments. As a representative immune escape mechanism, cancer-derived exosomes have recently been demonstrated to exhaust CD8⁺ cytotoxic T cells. Here, it is reported that sulfisoxazole, a sulfonamide antibacterial, significantly decreases the exosomal PD-L1 level in blood when orally administered to the tumor-bearing mice. Consequently, sulfisoxazole effectively reinvigorates exhausted T cells, thereby eliciting robust antitumor effects in combination with anti-PD-1 antibody. Overall, sulfisoxazole regulates immunosuppression through the inhibition of exosomal PD-L1, implying its potential to improve the response rate of anti-PD-1 antibodies.