特定的 BCL-2 小分子抑制剂 Venetoclax 可在多种恶性肿瘤中诱导细胞凋亡，这导致其单独使用以及与化疗和免疫疗法联合治疗多种癌症类型的临床应用迅速扩展。虽然淋巴细胞（尤其是 T 细胞）的生存和功能严重依赖 BCL-2，但 BCL-2 家族的小分子阻断对存活免疫细胞的影响尚不完全清楚。我们的目的是更好地了解 Venetoclax 全身治疗对调节性 T (Treg) 细胞的影响，与其他 T 细胞相比，调节性 T (Treg) 细胞对 BCL-2 特异性药物诱导的细胞死亡具有相对抵抗力。我们发现 BCL-2 阻断改变了 Treg 转录谱，并介导 Treg 可塑性向 TH17 样 Treg 表型发展，导致淋巴器官和肿瘤微环境内 IL-17A 的产生增加。与之前描述的将 Venetoclax 与抗 PD-1 检查点抑制相结合时观察到的增强抗肿瘤效果相一致，我们还证明 Treg 特异性基因 BCL-2 敲除与抗 PD-1 相结合可诱导肿瘤消退，并赋予 Venetoclax 重叠的基因变化。治疗Tregs。随着使用维奈托克的长期联合疗法在临床上获得更多关注，对维奈托克引起的免疫调节作用的进一步了解可能会扩大其针对恶性肿瘤和免疫相关疾病的用途。

The specific BCL-2 small molecule inhibitor venetoclax induces apoptosis in a wide range of malignancies, which has led to rapid clinical expansion in its use alone and in combination with chemotherapy and immune-based therapies against a myriad of cancer types. While lymphocytes, and T cells in particular, rely heavily on BCL-2 for survival and function, the effects of small molecule blockade of the BCL-2 family on surviving immune cells is not fully understood. We aimed to better understand the effect of systemic treatment with venetoclax on regulatory T (Treg) cells, which are relatively resistant to cell death induced by specific drugging of BCL-2 compared to other T cells. We found that BCL-2 blockade altered Treg transcriptional profiles and mediateed Treg plasticity towards a TH17-like Treg phenotype, resulting in increased IL-17A production in lymphoid organs and within the tumor microenvironment. Aligned with previously described augmented antitumor effects observed when combining venetoclax with anti-PD-1 checkpoint inhibition, we also demonstrated that Treg-specific genetic BCL-2 knockout combined with anti-PD-1 induced tumor regression and conferred overlapping genetic changes with venetoclax-treated Tregs. As long-term combination therapies using venetoclax gain more traction in the clinic, an improved understanding of the immune-modulatory effects caused by venetoclax may allow expansion of its use against malignancies and immune-related diseases.