The capacity of targeted anticancer agents to exert immunomodulatory effects provides a strong rationale to develop novel agents suitable for combinatorial regimens with immunotherapy to improve clinical outcomes. In this study, we developed a dual-targeting PI3K and HDAC inhibitor BEBT-908 that potently inhibits tumor cell growth and potentiates anti-PD1 therapy in mice by inducing immunogenic ferroptosis in cancer cells. Treatment with BEBT-908 promoted ferroptotic cell death of cancer cells by hyperacetylating p53 and facilitating the expression of ferroptotic signaling. Furthermore, BEBT-908 promoted a proinflammatory tumor microenvironment that activated host antitumor immune responses and potentiated immune checkpoint blockade therapy. Mechanistically, BEBT-908–induced ferroptosis led to upregulation of MHC class I and activation of endogenous IFNγ signaling in cancer cells via the STAT1 signaling pathway. The dual PI3K/HDAC inhibitor BEBT-908 is a promising targeted therapeutic agent against multiple cancer types that promotes immunogenic ferroptosis and enhances the efficacy of immunotherapy. Significance: The dual PI3K/HDAC inhibitor BEBT-908 elicits potent antitumor responses, effectively inducing immunogenic ferroptosis of tumor cells and potentiating cancer immunotherapy.

中文翻译：

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双 PI3K/HDAC 抑制剂可诱导免疫原性铁死亡以增强癌症免疫检查点治疗

BEBT-908 诱导的铁死亡通过 STAT1 信号通路导致癌细胞中 MHC I 类的上调和内源性 IFNγ 信号的激活。双重 PI3K/HDAC 抑制剂 BEBT-908 是一种很有前途的靶向治疗多种癌症类型的药物，可促进免疫原性铁死亡并增强免疫治疗的功效。意义：双重 PI3K/HDAC 抑制剂 BEBT-908 引发有效的抗肿瘤反应，有效诱导肿瘤细胞的免疫原性铁死亡并增强癌症免疫治疗。