高组蛋白去乙酰化酶2（HDAC2）表达增高是乳腺癌浸润的标志之一。HDAC2不仅促进肿瘤细胞的生长、发展和抗凋亡，还在调节肿瘤细胞表面的PD-L1中起着重要作用。持续的PD-L1表达使肿瘤细胞逃避了免疫监测。目前尚没有多少关于HDAC2如何影响乳腺癌免疫系统的研究。人参皂苷Rh4是经高温加工的人参中一种主要的稀有皂苷，因其强效药用价值和稳定的安全性而被广泛用于预防和治疗各种疾病。然而，Rh4如何影响乳腺癌的肿瘤免疫微环境仍不清楚。因此，本文旨在研究Rh4对乳腺癌中HDAC2的影响，特别是其对凋亡和免疫微环境的影响，以抑制乳腺癌生长。根据我们的研究，人参皂苷Rh4已被证明能显著抑制乳腺癌细胞增殖而没有任何不良影响。Rh4和HDAC2的分子对接结果表明结合能为-6.06 kcal/mol，提示Rh4具备作为HDAC2靶向调节剂的潜力。在机制上，Rh4通过HDAC2介导的caspase通路诱导乳腺癌细胞凋亡，抑制HDAC2介导的JAK/STAT通路来调节免疫微环境，从而抑制乳腺癌的生长。具体来说，Rh4首次被证明能抑制免疫检查点（PD-1/PD-L1）并增加肿瘤中T淋巴细胞的水平。总之，我们的研究建立了将Rh4作为乳腺癌治疗中免疫检查点抑制剂的理论框架。 版权所有©2023 Elsevier Inc.。

High expression of histone deacetylase 2 (HDAC2) is recognized as a marker of invasive breast cancer (BC). HDAC2 is not only responsible for enhancing tumor cell growth, development, and anti-apoptosis, but also plays a significant role in regulating PD-L1 on the surface of tumor cells. Continuous expression of PD-L1 allows tumor cells to escape immune surveillance. There is not much research on how HDAC2 affects the immune system in breast cancer. Ginsenoside Rh4 (Rh4) is a major rare saponin in heat-treated ginseng, which is widely applied in treating and preventing various diseases because of its potent medicinal value and stable safety. However, it is unclear how Rh4 affects the tumor immune microenvironment in breast cancer. Therefore, this paper aims to investigate the effect of Rh4 on HDAC2 in breast cancer, specifically the effect of HDAC2 on apoptosis and the immune microenvironment to inhibit breast cancer growth. According to our study, ginsenoside Rh4 has been shown to significantly suppress breast cancer cell proliferation without any adverse effects. The molecular docking results of Rh4 and HDAC2 indicate a binding energy of -6.06 kcal/mol, suggesting the potential of Rh4 as a targeting modulator of HDAC2. Mechanistically, Rh4 induces apoptosis of breast cancer cells by the HDAC2-mediated caspase pathway and inhibits the HDAC2-mediated JAK/STAT pathway to regulate the immune microenvironment, which inhibits breast cancer growth. Specifically, Rh4 was shown for the first time to blockade immune checkpoints (PD-1/PD-L1) and increase levels of T-lymphocytes in the tumor. In a word, our study establishes a theoretical framework for applying Rh4 as an immune checkpoint inhibitor as part of breast cancer treatment.Copyright © 2023 Elsevier Inc. All rights reserved.