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Here, we report a genome-wide CRISPR screen that revealed BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 enhanced DC antigen presentation and activation as well as the capacity of DCs to control tumors and to synergize with PD-1 blockade. The pharmacologic BCL2 inhibitors venetoclax and navitoclax phenocopied these effects and caused a cDC1-dependent regression of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to BCL2 inhibition in mice constitutively devoid of cDC1, and this was reversed by the infusion of DCs. Moreover, cDC1 depletion reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade and treatment with venetoclax caused cDC1 activation, both in mice and in patients. In conclusion, genetic and pharmacologic BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>BCL2 inhibition improves the capacity of DCs to stimulate anticancer immunity and restrain cancer growth in an immunocompetent context but not in mice lacking cDC1 or mature T cells. This study indicates that BCL2 blockade can be used to sensitize solid cancers to PD-1\/PD-L1\u2013targeting immunotherapy.<\/jats:p>\n                    <jats:p>This article is featured in Selected Articles from This Issue, p. 2293<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-22-1338","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T09:17:32Z","timestamp":1692955052000},"page":"2448-2469","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["BCL2 Inhibition Reveals a Dendritic Cell\u2013Specific Immune Checkpoint That Controls Tumor Immunosurveillance"],"prefix":"10.1158","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5077-327X","authenticated-orcid":false,"given":"Liwei","family":"Zhao","sequence":"first","affiliation":[{"name":"1Centre de Recherche des Cordeliers, Equipe Labellis\u00e9e par la Ligue contre le Cancer, Universit\u00e9 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M\u00e9decine, Universit\u00e9 de Paris Saclay, Kremlin Bic\u00eatre, France."},{"name":"5Department of Respiratory and Critical Care Medicine, Union Hospital, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2714-2087","authenticated-orcid":false,"given":"Camille","family":"Bigenwald","sequence":"additional","affiliation":[{"name":"6INSERM U1015, Equipe Labellis\u00e9e, Ligue Nationale contre le Cancer, Villejuif, France."},{"name":"7Gustave Roussy Cancer Campus, Villejuif Cedex, France."},{"name":"8Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7950-3652","authenticated-orcid":false,"given":"Charles-Antoine","family":"Dutertre","sequence":"additional","affiliation":[{"name":"6INSERM U1015, Equipe Labellis\u00e9e, Ligue Nationale contre le Cancer, Villejuif, France."},{"name":"7Gustave 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