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Syngeneic HCC mouse model is presented to explore the antitumor effect and safety of three sorafenib doses alone, R848 alone, or their combination in vivo. R848 significantly enhances the sorafenib antitumor activity at a low subclinical dose with no obvious toxic side effects. Furthermore, the combination therapy reprograms the tumor immune microenvironment by increasing antitumor macrophages and neutrophils and preventing immunosuppressive signaling. Combination treatment promotes classical M1 macrophage\u2010to\u2010FTH1<jats:sup>high<\/jats:sup> M1 macrophage transition. The close interaction between neutrophils\/classical M1 macrophages and dendritic cells promotes tumor antigen presentation to T cells, inducing cytotoxic CD8<jats:sup>+<\/jats:sup> T cell\u2010mediated antitumor immunity. Additionally, low\u2010dose sorafenib, alone or combined with R848, normalizes the tumor vasculature, generating a positive feedback loop to support the antitumor immune environment. Therefore, the combination therapy reprograms the HCC immune microenvironment and normalizes the vasculature, improving the therapeutic benefit of low\u2010dose sorafenib and minimizing toxicity, suggesting a promising novel immunotherapy (R848) and targeted therapy (tyrosine kinase inhibitors) combination strategy for HCC treatment.<\/jats:p>","DOI":"10.1002\/advs.202207650","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T07:50:51Z","timestamp":1682063451000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["The Combination of R848 with Sorafenib Enhances Antitumor Effects by Reprogramming the Tumor Immune Microenvironment and Facilitating Vascular Normalization in Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"10","author":[{"given":"Yuchao","family":"He","sequence":"first","affiliation":[{"name":"Department of Tumor Cell Biology Tianjin Medical University Cancer 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