我们开发了一个用于功能探索树突状细胞（DC）的表型筛选平台。在这里，我们报道了一个全基因组CRISPR筛选，发现BCL2是DC功能的内源性抑制剂。BCL2的敲除增强了DC的抗原呈递和激活能力，以及DC控制肿瘤和与PD-1阻断协同作用的能力。药物BCL2抑制剂 Venetoclax 和 Navitoclax 的表型同这些效应相似，并引起依赖于 cDC1 的原位肺癌和纤维肉瘤的逆转。因此，缺乏 cDC1 的小鼠体内的实体肿瘤对 Bcl2 抑制剂不产生反应，而注入 DC 则可以扭转这一现象。此外，cDC1 耗竭降低了单独使用或与 PD-1阻断和 Venetoclax 联合治疗的 BCL2 抑制剂的治疗效果，并且 Venetoclax 的治疗导致了 cDC1 的激活，无论是在小鼠还是患者体内。总之，遗传学和药理学上的 BCL2 抑制揭示了一种特异性于 DC，对肿瘤免疫监视起限制作用的免疫检查点。

We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). 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 pharmacological 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 pharmacological BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance.