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However, recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment (TME) after oncolysis-mediated local inflammation leads to tumor resistance to the therapy. Using the murine malignant mesothelioma model, we demonstrated that the in situ vaccinia virotherapy recruited primarily polymorphonuclear MDSCs (PMN-MDSCs) into the TME, where they exhibited strong suppression of cytotoxic T lymphocytes in a reactive oxygen species\u2013dependent way. Single-cell RNA sequencing analysis confirmed the suppressive profile of PMN-MDSCs at the transcriptomic level and identified CXCR2 as a therapeutic target expressed on PMN-MDSCs. Abrogating PMN-MDSC trafficking by CXCR2-specific small molecule inhibitor during the vaccinia virotherapy exhibited enhanced antitumor efficacy in 3 syngeneic cancer models, through increasing CD8+\/MDSC ratios in the TME, activating cytotoxic T lymphocytes, and skewing suppressive TME into an antitumor environment. Our results warrant clinical development of CXCR2 inhibitor in combination with oncolytic virotherapy.<\/jats:p>","DOI":"10.1093\/jleuko\/qiad150","type":"journal-article","created":{"date-parts":[[2023,12,9]],"date-time":"2023-12-09T04:21:08Z","timestamp":1702095668000},"page":"633-646","source":"Crossref","is-referenced-by-count":4,"title":["Enhancing the efficacy of vaccinia-based oncolytic virotherapy by inhibiting CXCR2-mediated MDSC trafficking"],"prefix":"10.1093","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3560-6884","authenticated-orcid":false,"given":"Zhiwu","family":"Tan","sequence":"first","affiliation":[{"name":"AIDS Institute and Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong , 21 Sassoon Road, Pokfulam, Hong Kong SAR , People's Republic of China"},{"name":"Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science 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