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Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47\/SIRP\u03b1 and TIGIT\/PVR pathways has not been investigated. Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRP\u03b1 and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47\/SIRP\u03b1 and TIGIT\/PVR pathways by co-targeting SIRP\u03b1 and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8+ T cell in tumor and systematic immune response in the tumor-draining lymph node and spleen in a CD8+ T cell dependent manner. Our research suggests that the anti-hypertensive drug azelnidipine could be repositioned for cancer immunotherapy.<\/jats:p>","DOI":"10.3390\/biom11050706","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T05:30:08Z","timestamp":1620624608000},"page":"706","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Repositioning Azelnidipine as a Dual Inhibitor Targeting CD47\/SIRP\u03b1 and TIGIT\/PVR Pathways for Cancer Immuno-Therapy"],"prefix":"10.3390","volume":"11","author":[{"given":"Xiuman","family":"Zhou","sequence":"first","affiliation":[{"name":"Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518035, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Jiao","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuzhen","family":"Qian","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingyu","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixuan","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8942-1543","authenticated-orcid":false,"given":"Wei V.","family":"Zheng","sequence":"additional","affiliation":[{"name":"Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518035, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenshan","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjie","family":"Zhai","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6381-611X","authenticated-orcid":false,"given":"Yahong","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongfei","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanfeng","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junhui","family":"Chen","sequence":"additional","affiliation":[{"name":"Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518035, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10501","DOI":"10.1038\/ncomms10501","article-title":"Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints","volume":"7","author":"Koyama","year":"2016","journal-title":"Nat. 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