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Here, we report two ICP6\u2010mutated HSVs (type I) generated by CRISPR\/Cas9, rHSV1\/\u2206RR (with ICP6 ribonucleotide reductase [RR]\u00a0domain deleted) and rHSV1\/\u2206ICP6 (with a complete deletion of ICP6), exhibiting potent antitumor efficacy against lung adenocarcinoma. Both the mutants showed strong cytotoxicity in vitro, comparable with the control viruses expressing intact ICP6, but in relatively lower titers. Moreover, these mutant viruses exhibited preferential killing ability against lung tumor cells rather than normal lung fibroblast cells. Further, unlike the control HSV\u20101 causing severe illness or death in the mouse model, the ICP6\u2010mutated viruses did not induce significant pathogenicity but instead effectively reduced tumor burden in vivo and led to 100% survival of the animals, indicating notable antitumor activity and attenuated virulence. In addition, rHSV1\/\u2206RR seemed to have even better antitumor efficacy than rHSV1\/\u2206ICP6, albeit no statistical significance in inhibition of tumor volume. Histopathologically, rHSV1\/\u2206RR induced massive neutrophil infiltration to the tumor microenvironment and consistently, triggered more antitumor immune and neutrophil chemotactic cytokines or higher expression levels of them (indicated by quantitative polymerase chain reaction and transcriptome analyses). These results demonstrate the anti\u2010adenocarcinoma potential of the CRISPR\/Cas9\u2010engineered ICP6 mutant HSV1, especially the rHSV1\/\u2206RR, which likely induces stronger innate antitumor immune response. Together, these findings may provide new valuable clues for further development of OV\u2010based therapeutics against lung adenocarcinoma or other types of tumors.<\/jats:p>","DOI":"10.1002\/jmv.28069","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T03:19:12Z","timestamp":1660533552000},"page":"6000-6015","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Antitumor efficacy of CRISPR\/Cas9\u2013engineered ICP6 mutant herpes simplex viruses in a mouse xenograft model for lung adenocarcinoma"],"prefix":"10.1002","volume":"94","author":[{"given":"Longquan","family":"Ni","sequence":"first","affiliation":[{"name":"State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology Chinese Academy of Sciences Wuhan China"},{"name":"University of Chinese Academy of Sciences Beijing 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