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To address this issue, we engineered an oncolytic vaccinia virus to express HSP70 shRNA within its TK gene locus (oncoVV\u2010shHSP70). In\u00a0vitro, oncoVV\u2010shHSP70 significantly suppressed HSP70 expression, enhanced viral replication, and induced apoptosis in CRC cells via Caspase\u20107\/9 activation and Bcl\u20102 downregulation. OncoVV\u2010shHSP70 also triggered reactive oxygen species (ROS) accumulation by suppressing the antioxidant regulator Nrf2 and stimulated autophagy via the Beclin\u20101\/Vps34 pathway. Notably, a mutually reinforcing cycle between ROS overproduction and autophagy amplified the oncolytic effects of oncoVV\u2010shHSP70, enhancing viral production, promoting apoptosis, and increasing cytokine release. Specifically, oncoVV\u2010shHSP70 boosted cytokine production (TNF\u2010\u03b1, IFN\u2010\u03b1\/\u03b2) through ROS\/autophagy\u2010dependent activation of AP\u20101 and IRF\u20103\/7 pathways. In xenograft mouse models, oncoVV\u2010shHSP70 induced cellular necrosis and significantly inhibited tumor growth. These findings demonstrate that oncoVV\u2010shHSP70 enhances antitumor immunity in both syngeneic and humanized mouse models by promoting T\u2010cell and dendritic\u2010cell infiltration and inducing immunogenic cell death. In summary, oncoVV\u2010shHSP70 emerges as a promising multimodal therapy for CRC, leveraging viral oncolysis, apoptosis induction, and immunomodulation to overcome therapeutic resistance.<\/jats:p>","DOI":"10.1111\/cas.70389","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T07:19:17Z","timestamp":1776928757000},"page":"2007-2020","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Oncolytic Vaccinia Virus\u2010\n                    <scp>HSP70<\/scp>\n                    \u2010\n                    <scp>shRNA<\/scp>\n                    Amplifies Viral Replication,\n                    <scp>ROS<\/scp>\n                    \/Autophagy, and Immunity to Fight Colorectal Cancer"],"prefix":"10.1111","volume":"117","author":[{"given":"Rentao","family":"Yuan","sequence":"first","affiliation":[{"name":"College of Life Sciences and Medicine Zhejiang Sci\u2010Tech University  Hangzhou 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