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The therapy accumulates ROS by inhibiting Nrf2, activates autophagy through Beclin-1/Vps34, and forms a ROS-autophagy loop that amplifies viral production, apoptosis, and cytokine release, culminating in robust antitumor immunity and tumor suppression in mouse models.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/inflammation-and-virology-oncolytic-vaccinia-virus-hsp70-shrna-amplifies-viral-replication-rosautophagy-and-immunity-to-fight-colorectal-cancer/357425/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/inflammation-and-virology-oncolytic-vaccinia-virus-hsp70-shrna-amplifies-viral-replication-rosautophagy-and-immunity-to-fight-colorectal-cancer/357425.png","ImageObject",300,407,{"name":42,"@type":43},"Bulrr","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-28","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",10,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What therapeutic strategy is used to target colorectal cancer in this study?","Question",{"text":63,"@type":64},"The study engineers an oncolytic vaccinia virus to express HSP70 shRNA at the TK gene locus (oncoVV-shHSP70).","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does oncoVV-shHSP70 suppress CRC cells?",{"text":68,"@type":64},"It downregulates HSP70, enhances viral replication, and induces apoptosis via Caspase-7/9 activation and Bcl-2 downregulation.",{"name":70,"@type":61,"acceptedAnswer":71},"What roles do ROS and autophagy play in the antitumor effect?",{"text":72,"@type":64},"oncoVV-shHSP70 increases ROS by suppressing Nrf2 and stimulates autophagy via the Beclin-1/Vps34 pathway; 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To address this issue, we engineered an oncolytic vaccinia virus to express HSP70 shRNA within its TK gene locus (oncoVV-shHSP70) . In vitro, oncoVV-shHSP70 significantly suppressed HSP70 expression, enhanced viral replication, and induced apoptosis in CRC cells via Caspase-7/9 activation and Bcl-2 downregulation. OncoVV-shHSP70 also triggered reactive oxygen species (ROS) accumulation by suppressing the antioxidant regulator Nrf2 and stimulated autophagy via the Beclin-1/Vps34 pathway. Notably, a mutually reinforcing cycle between ROS overproduction and autophagy amplified the oncolytic effects of oncoVV-shHSP70, enhancing viral production, promoting apoptosis, and increasing cytokine release. Specifically, oncoVV-shHSP70 boosted cytokine production (TNF-α, IFN-α/β) through ROS/autophagy-dependent activation of AP-1 and IRF-3/7 pathways. In xenograft mouse models, oncoVV-shHSP70 induced cellular necrosis and significantly inhibited tumor growth. These findings demonstrate that oncoVV-shHSP70 enhances antitumor immunity in both syngeneic and humanized mouse models by promoting T-cell and dendritic-cell infiltration and inducing immunogenic cell death. In summary, oncoVV-shHSP70 emerges as a promising multimodal therapy for CRC, leveraging viral oncolysis, apoptosis induction, and immunomodulation to overcome therapeutic resistance.  \n1 | Introduction  \nRanking third among malignancies globally, colorectal cancer (CRC) causes 1.9 million new cases and one in ten cancer deaths annually [1, 2] . Although the incidence of CRC has decreased, 20% ofCRC patients still have synchronous metastases, and 40% of CRC patients develop metastatic disease [3] . Of note, patients with advanced CRC exhibit persistently low five-year survival rates (10%–30%). Immunotherapy shows promise in malignancy  \ntreatment but faces limited efficacy in cold CRC due to immune escape mechanisms [4] . Given the limitations of current therapies for CRC, innovative therapeutic strategies are urgently needed.  \nOncolytic viruses (OVs) represent a novel class of immunotherapeutics that promote anti-tumor responses via two primary mechanisms: direct lysis via oncotropic replication, and the stimulation of systemic anti-tumor immunity [5–7] . To  \n\n| Abbreviations: 3-MA, 3-methyladenine; AP-1, activator protein-1; CQ, chloroquine; CRC, colorectal cancer; HSP70, heat shock protein 70; IFN-α, interferon-α; IFN-β, interferon-β; IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7; MOI, multiplicity of infection; OncoVV, oncolytic vaccinia virus; OVs, oncolytic viruses; PBMCs, human peripheral blood mononuclear cells; ROS, reactive oxygen species; TME, tumor microenvironment; TNF-α, tumor necrosis factor-α .\u003Cbr>Rentao Yuan and Ruikang Liu contributed equally to this work. |\n| --- |\n| This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\u003Cbr>© 2026 The Author(s). Cancer Science published by John Wiley & Sons Australia,","cbCaikCUj4avnEZN","https://ap.wps.com/l/cbCaikCUj4avnEZN","pdf",11948859,14,"English","# Introduction\n## Oncolytic viruses and immunotherapy rationale\n## Vaccinia virus as an oncolytic platform\n# Background on HSP70 and stress response","[{\"question\":\"What therapeutic strategy is used to target colorectal cancer in this study?\",\"answer\":\"The study engineers an oncolytic vaccinia virus to express HSP70 shRNA at the TK gene locus (oncoVV-shHSP70).\"},{\"question\":\"How does oncoVV-shHSP70 suppress CRC cells?\",\"answer\":\"It downregulates HSP70, enhances viral replication, and induces apoptosis via Caspase-7/9 activation and Bcl-2 downregulation.\"},{\"question\":\"What roles do ROS and autophagy play in the antitumor effect?\",\"answer\":\"oncoVV-shHSP70 increases ROS by suppressing Nrf2 and stimulates autophagy via the Beclin-1/Vps34 pathway; a reinforcing ROS-autophagy cycle amplifies viral production, apoptosis, and cytokine release.\"}]","Inflammation and Virology - Oncolytic Vaccinia Virus-HSP70-shRNA Amplifies Viral Replication, ROS/Autophagy, and Immunity to Fight Colorectal Cancer | PDF",1790129995,35]