Wang Wenhua, Li Xin, Hu Rui, Dong Liang, Pei Shiyao, Jin Liping, Gao Qian, Chen Xiang, Yin Mingzhu
Department of Intensive Care Unit, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC), Chongqing University Three Gorges Hospital, Chongqing University, Wanzhou, Chongqing 404100, China; Translational Medicine Research Center (TMRC), School of Medicine Chongqing University, Shapingba, Chongqing 400000, China.
Cell Rep Med. 2025 Mar 18;6(3):101995. doi: 10.1016/j.xcrm.2025.101995.
Immunotherapy shows remarkable benefits in treating melanoma, yet existing approaches achieve limited overall responses. Here, we show that a combination of bromodomain and extra-terminal protein family inhibitor, NHWD-870, and Bacillus Calmette-Guérin vaccine is a promising therapeutic strategy for melanomas. Single-cell transcriptome analyses and functional experiments show that the combination therapy significantly inhibited tumor growth by reprogramming T cells toward an immune-activated state, enhancing their cytotoxicity, preventing their exhaustion, and increasing the recruitment of them into the tumor microenvironment. We identify the molecule, MT1, as a direct downstream target of BRD4, which is effectively suppressed by NHWD-870. Furthermore, our findings are reinforced by a humanized patient-derived xenograft (PDX) model, which exhibits notable antitumor effects in humanized tumor-bearing mice treated with the combination therapy. Our study underscores the immense potential of this therapeutic approach for clinical practice, offering promising prospects in overcoming the limitations of current treatments.
免疫疗法在治疗黑色素瘤方面显示出显著疗效，但现有方法的总体反应有限。在此，我们表明，溴结构域和额外末端蛋白家族抑制剂NHWD-870与卡介苗疫苗联合使用是一种有前景的黑色素瘤治疗策略。单细胞转录组分析和功能实验表明，联合疗法通过将T细胞重编程为免疫激活状态、增强其细胞毒性、防止其耗竭以及增加其向肿瘤微环境的募集，显著抑制了肿瘤生长。我们确定分子MT1是BRD4的直接下游靶点，NHWD-870可有效抑制该靶点。此外，人源化患者来源异种移植（PDX）模型强化了我们的研究结果，该模型在用联合疗法治疗的人源化荷瘤小鼠中表现出显著的抗肿瘤作用。我们的研究强调了这种治疗方法在临床实践中的巨大潜力，为克服当前治疗的局限性提供了有前景的前景。
