BET inhibition has been shown to have a promising antitumor effect in multiple tumors. However, the impact of BET inhibition on antitumor immunity was still not well documented in HNSCC. In this study, we aim to assess the functional role of BET inhibition in antitumor immunity and clarify its mechanism. We show that BRD4 is highly expressed in HNSCC and inversely correlated with the infiltration of CD8⁺ T cells. BET inhibition potentiates CD8⁺ T cell-based antitumor immunity in vitro and in vivo. Mechanistically, BRD4 acts as a transcriptional suppressor and represses the expression of MHC class I molecules by recruiting G9a. Pharmacological inhibition or genetic depletion of BRD4 potently increases the expression of MHC class I molecules in the absence and presence of IFN-γ. Moreover, compared to PD-1 blocking antibody treatment or JQ1 treatment individually, the combination of BET inhibition with anti-PD-1 antibody treatment significantly enhances the antitumor response in HNSCC. Taken together, our data unveil a novel mechanism by which BET inhibition potentiates antitumor immunity via promoting the expression of MHC class I molecules and provides a rationale for the combination of ICBs with BET inhibitors for HNSCC treatment.

BET 抑制已被证明在多种肿瘤中具有良好的抗肿瘤作用。然而，BET 抑制对 HNSCC 抗肿瘤免疫的影响尚未得到充分记录。在本研究中，我们旨在评估 BET 抑制在抗肿瘤免疫中的功能作用并阐明其机制。^{我们发现 BRD4 在 HNSCC 中高表达，并且与 CD8 +} T 细胞的浸润呈负相关。BET 抑制可增强基于 CD8 ⁺ T 细胞的体外和体内抗肿瘤免疫。从机制上讲，BRD4 作为转录抑制因子，通过招募 G9a 来抑制 MHC I 类分子的表达。在 IFN-γ 不存在和存在的情况下，BRD4 的药理学抑制或基因缺失可有效增加 MHC I 类分子的表达。此外，与单独的PD-1阻断抗体治疗或JQ1治疗相比，BET抑制与抗PD-1抗体治疗的组合显着增强了HNSCC的抗肿瘤反应。总而言之，我们的数据揭示了一种新机制，BET 抑制通过促进 MHC I 类分子的表达来增强抗肿瘤免疫，并为 ICB 与 BET 抑制剂联合治疗 HNSCC 提供了理论依据。