He Kai-Yue, Zhao Annie, Guo Jin-Rong, Wu Dan-Hui, Liu Huai, Gao Fan, Liu Meng-Jie, Yang Jing-Yu, Lei Xin-Yuan, Li Jun-Qi, Zhang Lei, Yan Zhen-Hua, Ding Qiang, Huang Yong-Wei, Cui Rutao, Jian Yong-Ping, Xu Zhi-Xiang
School of Life Sciences, Henan University, Kaifeng, Henan Province, 475000, China.
Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Nat Commun. 2025 Jun 2;16(1):5098. doi: 10.1038/s41467-025-60221-6.
Esophageal squamous cell carcinoma (ESCC) is a common and aggressive cancer with limited responses to immunotherapy. High mobility group A1 (HMGA1), a chromatin remodeling protein, plays a key role in tumor progression, but its impact on anti-tumor immunity in ESCC remains unclear. Here we show that HMGA1 suppresses the stimulator of interferon genes (STING), inhibiting type I interferon secretion, downregulating interferon-stimulated genes, and impairing tumor-infiltrating lymphocyte (TIL) recruitment. HMGA1 inhibits STING transcription by competing with the coactivator CBP/p300 for binding to CREB. ESCCs from genetically modified mouse models with altered HMGA1 and STING expression exhibit varying TIL levels and sensitivity to STING agonists. Additionally, we design and synthesize a series of HMGA1 inhibitors, including a perylene-based nanoparticle, PDIC-DPC, which effectively inhibits HMGA1 and enhances TIL infiltration. Our findings identify HMGA1 as a critical immune checkpoint in ESCC and suggest that targeting HMGA1 could improve immunotherapy outcomes.
食管鳞状细胞癌（ESCC）是一种常见的侵袭性癌症，对免疫疗法反应有限。高迁移率族蛋白A1（HMGA1）是一种染色质重塑蛋白，在肿瘤进展中起关键作用，但其对ESCC抗肿瘤免疫的影响仍不清楚。在此，我们表明HMGA1抑制干扰素基因刺激物（STING），抑制I型干扰素分泌，下调干扰素刺激基因，并损害肿瘤浸润淋巴细胞（TIL）募集。HMGA1通过与共激活因子CBP/p300竞争结合CREB来抑制STING转录。来自基因改造小鼠模型的ESCC，其HMGA1和STING表达发生改变，表现出不同的TIL水平和对STING激动剂的敏感性。此外，我们设计并合成了一系列HMGA1抑制剂，包括一种基于苝的纳米颗粒PDIC-DPC，它能有效抑制HMGA1并增强TIL浸润。我们的研究结果确定HMGA1是ESCC中的一个关键免疫检查点，并表明靶向HMGA1可改善免疫治疗效果。
