纵向血浆代谢组学指导食管鳞状细胞癌化疗免疫治疗的动态风险评估与饮食调节
Longitudinal Plasma Metabolomics Guides Dynamic Risk Assessment and Dietary Modulation for Esophageal Squamous Cell Cancer Chemoimmunotherapy.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
高迁移率族蛋白 A1（HMGA1）通过抑制 STING 介导的抗肿瘤免疫促进食管鳞状细胞癌进展
英文原题：High mobility group A1 (HMGA1) promotes esophageal squamous cell carcinoma progression by inhibiting STING-mediated anti-tumor immunity.
查看英文原题
High mobility group A1 (HMGA1) promotes esophageal squamous cell carcinoma progression by inhibiting STING-mediated anti-tumor immunity.
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中文摘要
食管鳞状细胞癌（ESCC）是一种常见且侵袭性强的癌症，对免疫治疗的应答有限。高迁移率族蛋白A1（HMGA1）是一种染色质重塑蛋白，在肿瘤进展中发挥关键作用，但其对ESCC抗肿瘤免疫的影响尚不清楚。我们发现，HMGA1可抑制干扰素基因刺激因子（STING），从而抑制I型干扰素分泌、下调干扰素刺激基因并损害TIL（肿瘤浸润淋巴细胞）的募集。HMGA1通过与共激活因子CBP/p300竞争结合CREB，抑制STING转录。HMGA1和STING表达经改造的基因工程小鼠模型来源ESCC表现出不同的TIL水平及对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；该颗粒可有效抑制HMGA1并增强TIL浸润。研究结果确定HMGA1是ESCC中的关键免疫检查点，并提示靶向HMGA1可能改善免疫治疗结局。
展开英文摘要原文
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.
论文信息
- 作者
- He KY、Zhao A、Guo JR、Wu DH、Liu H、Gao F、Liu MJ、Yang JY
- 第一作者单位
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475000, China.China
- 通讯作者单位
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475000, China. zhixiangxu08@gmail.com.China
- 期刊
- Nature communications2025 Jun 2
- 原文标识
- PubMed 40456764 · DOI 10.1038/s41467-025-60221-6
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