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Viral expression of NE/PPE enhances anti-colorectal cancer efficacy of oncolytic adenovirus by promoting TAM M1 polarization to reverse insufficient effector memory/effector CD8+ T cell infiltration

Shuo WangJiangsu Key Laboratory of Molecular Medicine, Medical School, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, Nanjing, 210093, ChinaLingkai KongJiangsu Key Laboratory of Molecular Medicine, Medical School, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, Nanjing, 210093, ChinaLinpei WangDepartment of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, ChinaYan ZhuangJiangsu Key Laboratory of Molecular Medicine, Medical School, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, Nanjing, 210093, ChinaCiliang GuoJiangsu Key Laboratory of Molecular Medicine, Medical School, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, Nanjing, 210093, ChinaYuxin ZhangJiangsu Key Laboratory of Molecular Medicine, Medical School, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, Nanjing, 210093, ChinaHuawei CuiJiangsu Key Laboratory of Molecular Medicine, Medical School, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, Nanjing, 210093, ChinaXiaosong GuJinan Microecological Biomedicine Shandong Laboratory, Jinan, 250021, China. [email protected]Junhua WuJiangsu Key Laboratory of Molecular Medicine, Medical School, National Institute of Healthcare Data Science at Nanjing University, Nanjing University, Nanjing, 210093, China. [email protected]Chunping JiangDepartment of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, China. [email protected]

2025en

ABI

Annotatsiya

Abstract Background Oncolytic adenoviruses are among the most widely utilized oncolytic viruses due to their notable anti-tumor and gene expression capabilities, and modification of ADVs to create armed adenoviruses remains a popular research direction. Nonetheless, immune suppression triggered by ADV and targeted enhancements based on this limitation have been relatively unexplored. Methods Flow cytometry was employed to assess immune infiltration in the tumor microenvironment following ADV therapy. Targeted novel recombinant oncolytic viruses, ADV NE and ADV PPE , were designed, and their antitumor efficacy, safety, and ability to reshape immune infiltration were evaluated in both subcutaneous tumor models in mice and in vitro experiments. Immune cell depletion assays confirmed the critical role of macrophages. The impact of HMGB1 on macrophage polarization was investigated using shRNA, qRT-PCR, ELISA, and flow cytometry. Furthermore, the importance of TLR4 and its downstream pathways was validated through immunoprecipitation, Western blotting, homozygous knockout mice, and TLR4 inhibitors. Results We demonstrated that ADV limits the infiltration of effector memory/effector CD8 + T cells (T EM /T E ) within the tumor microenvironment. To address this, we leveraged the strong capacity of NE or PPE to recruit T EM /T E by constructing novel recombinant oncolytic adenoviruses, ADV NE or ADV PPE , armed with NE or PPE. These recombinant viruses induce pyroptosis in colorectal cancer cells accompanied by the release of HMGB1. HMGB1 binds to TLR4 on the surface of macrophages, activating the MyD88-NFκB-NLRP3 (ASC) pathway and promoting M1 polarization of TAMs, thereby increasing T EM /T E cell infiltration and enhancing antitumor efficacy. Conclusions In summary, this study presents the development of the novel oncolytic adenoviruses ADV NE and ADV PPE with enhanced anti-tumor efficacy and provides an in-depth exploration of their specific anti-tumor mechanisms. These findings indicate promising clinical therapeutic prospects and offer new insights for advancing oncolytic adenovirus therapies.

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DOI: 10.1186/s13046-025-03358-y

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