Wang Min, Chen Yanxing, Tian Lin, Wu Chenyi, Chen Jiaying, Hu Jiajia, Huang Runjie, Wang Yingnan, Zhang Jinling, Ouyang Xiao-Jie, Wang Liqin, Jin Ying, Zhao Qi, Wang Feng, Xu Rui-Hua
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, P. R. China.
Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P. R. China.
Cancer Discov. 2025 Sep 4;15(9):1883-1904. doi: 10.1158/2159-8290.CD-24-1033.
Immunotherapy has made remarkable strides in the treatment of solid tumors, but its efficacy as a single agent in immunologically cold tumors remains limited. Therefore, it is necessary to explore novel drug combinations to further optimize immunotherapy. Herein, we demonstrated that the histone deacetylase inhibitor (HDACi) chidamide enhanced chromatin accessibility at the promoters of genes that encode effector molecules in CD8+ T cells, thereby augmenting their antitumor capabilities. However, HDACi also induced the expression of VEGFA in protumorigenic macrophages, which led to vascular abnormalization and hindered immune cell infiltration, compromising its potential synergistic effect with immunotherapy. Accordingly, combining antiangiogenic therapy counteracted the angiogenic effects of HDACi, collaboratively unleashing the infiltration and functionality of cytotoxic CD8+ T cells. These findings were confirmed by single-cell RNA sequencing data from our patient samples. Thus, through mechanistic research, we propose a new therapeutic approach by the combination of HDACi, antiangiogenic therapy, and immunotherapy, highlighting its potential application across diverse solid tumors.
The challenges of tumor therapy primarily lie in developing novel intervention strategies to shift the tumor microenvironment toward an antitumor phenotype. Herein, we discovered that the combination of HDACi and antiangiogenic therapy promoted the functionality and infiltration of CD8+ T cells, ultimately remodeling the tumor microenvironment and boosting immunotherapy efficacy.
免疫疗法在实体瘤治疗方面取得了显著进展，但其作为单一药物在免疫冷肿瘤中的疗效仍然有限。因此，有必要探索新的药物组合以进一步优化免疫疗法。在此，我们证明组蛋白去乙酰化酶抑制剂（HDACi）西达本胺增强了CD8 + T细胞中编码效应分子的基因启动子处的染色质可及性，从而增强了它们的抗肿瘤能力。然而，HDACi还诱导促肿瘤巨噬细胞中VEGFA的表达，这导致血管异常并阻碍免疫细胞浸润，损害了其与免疫疗法的潜在协同效应。因此，联合抗血管生成疗法抵消了HDACi的血管生成作用，协同释放细胞毒性CD8 + T细胞的浸润和功能。我们患者样本的单细胞RNA测序数据证实了这些发现。因此，通过机制研究，我们提出了一种由HDACi、抗血管生成疗法和免疫疗法联合的新治疗方法，突出了其在多种实体瘤中的潜在应用。
肿瘤治疗的挑战主要在于开发新的干预策略，使肿瘤微环境向抗肿瘤表型转变。在此，我们发现HDACi与抗血管生成疗法的联合促进了CD8 + T细胞的功能和浸润，最终重塑了肿瘤微环境并提高了免疫治疗效果。
