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Cytotoxic lymphocyte trafficking into tumours is critical for the success of ICB. Therefore, additional strategies that increase cytotoxic lymphocyte trafficking into tumours are urgently needed to improve patient immune responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Paired adjacent tissue and cancerous lesions with HBV\u2010associated HCC were subjected to RNA\u2010seq analysis. Bone morphogenetic protein (BMP9), which reflects vessel normalisation, was identified through Cytoscape software, clinical specimens and Gene Expression Omnibus (GEO) datasets for HCC. The functional effects and mechanism of BMP9 on the tumour vasculature were evaluated in cells and animals. An ultrasound\u2010targeted microbubble destruction (UTMD)\u2010mediated BMP9 delivery strategy was used to normalise the vasculature and evaluate therapeutic efficacy mediated by cytotoxic lymphocytes (NK cells) in combination with a PD\u2010L1 antibody in human cancer xenografts of immune\u2010deficient mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We discovered that hepatitis B virus (HBV) infection\u2010induced downregulation of BMP9 expression correlated with a poor prognosis and pathological vascular abnormalities in patients with HCC. BMP9 overexpression in HBV\u2010infected HCC cells promoted intra\u2010tumoural cytotoxic lymphocyte infiltration via vascular normalisation by inhibiting the Rho\u2010ROCK\u2010myosin light chain (MLC) signalling cascade, resulting in enhanced efficacy of immunotherapy. Furthermore, UTMD\u2010mediated BMP9 delivery restored the anti\u2010tumour function of cytotoxic lymphocytes (NK cells) and showed therapeutic efficacy in combination with a PD\u2010L1 antibody in human cancer xenografts of immune\u2010deficient mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>HBV\u2010induced BMP9 downregulation causes vascular abnormalities that inhibit intra\u2010tumoural cytotoxic lymphocyte infiltration, providing a rationale for developing and combining immunotherapy with BMP9\u2010based therapy to treat HBV\u2010associated HCC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1247","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T06:36:17Z","timestamp":1683095777000},"source":"Crossref","is-referenced-by-count":5,"title":["BMP9\u2010induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus\u2010associated hepatocellular carcinoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Yulong","family":"Han","sequence":"first","affiliation":[{"name":"Department of Experimental Research State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Sun Yat\u2010sen University Cancer Center  Guangzhou Guangdong P. 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