DNA损伤修复（DDR）是一种维持基因组完整性并在细胞和有机体水平上发挥重要作用的关键过程。在这里，我们旨在描绘食管鳞状细胞癌（ESCC）的DDR特征、研究DDR相关特征的预后价值，并探索其指导个体化治疗策略的潜力。我们分析了来自我院和其他公开可获得的队列共计377个ESCC病例的批量和单细胞转录组数据，以识别主要DDR亚型。通过免疫基因组分析和体外实验，研究了这些DDR亚型在细胞和功能特性、肿瘤微环境（TME）特征和预后意义方面的异质性。此外，我们通过实验证实了一种组合免疫疗法策略，使用ESCC的同基因小鼠模型。DDR损伤特征分析使我们能够确定两种明显不同的DDR亚型，DDR活跃和DDR静默，这两种亚型在局部ESCC中具有独立的预后价值，而在转移性ESCC中则没有。DDR静默亚型的特征是充满炎症但免疫抑制的微环境，具有相对较高的免疫细胞浸润、异常的免疫检查点表达、T细胞衰竭以及癌相关通路的富集。此外，DDR亚型提示BRCA1和HFM1是局部ESCC中稳健独立的预后因子。最后，我们提出并验证了在高风险局部ESCC肿瘤中同时激活GITR或阻断BTLA与PD-1阻断或顺铂化疗的组合策略表示有效。我们基于DDR的分子亚型的发现将提升我们对肿瘤异质性的认识，并对局部ESCC的治疗和管理策略产生重大临床意义。本研究得到了中国国家重点研发计划（2021YFC2501000，2022YFC3401003）、国家自然科学基金（82172882）、北京自然科学基金（7212085）、中国医学科学院创新基金（2021-I2M-1-018，2021-I2M-1-067）、中央高校基本科研业务费（3332021091）和中国医学科学院非盈利中央研究所基金（2019PT310027）的支持。版权所有 © 2023 作者。Elsevier B.V.发表并保留全部权利。

DNA damage repair (DDR) is a critical process that maintains genomic integrity and plays essential roles at both the cellular and organismic levels. Here, we aimed to characterize the DDR profiling of esophageal squamous cell carcinoma (ESCC), investigate the prognostic value of DDR-related features, and explore their potential for guiding personalized treatment strategies.We analyzed bulk and single-cell transcriptomics data from 377 ESCC cases from our institution and other publicly available cohorts to identify major DDR subtypes. The heterogeneity in cellular and functional properties, tumor microenvironment (TME) characteristics, and prognostic significance of these DDR subtypes were investigated using immunogenomic analysis and in vitro experiments. Additionally, we experimentally validated a combinatorial immunotherapy strategy using syngeneic mouse models of ESCC.DDR alteration profiling enabled us to identify two distinct DDR subtypes, DDRactive and DDRsilent, which exhibited independent prognostic values in locoregional ESCC but not in metastatic ESCC. The DDRsilent subtype was characterized by an inflamed but immune-suppressed microenvironment with relatively high immune cell infiltration, abnormal immune checkpoint expression, T-cell exhaustion, and enrichment of cancer-related pathways. Moreover, DDR subtyping indicates that BRCA1 and HFM1 are robust and independent prognostic factors in locoregional ESCC. Finally, we proposed and verified that the concomitant triggering of GITR or blockade of BTLA with PD-1 blockade or cisplatin chemotherapy represents effective combination strategies for high-risk locoregional ESCC tumors.Our discovery of DDR-based molecular subtypes will enhance our understanding of tumor heterogeneity and have significant clinical implications for the therapeutic and management strategies of locoregional ESCC.This study was supported by the National Key R&D Program of China (2021YFC2501000, 2022YFC3401003), National Natural Science Foundation of China (82172882), the Beijing Natural Science Foundation (7212085), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018, 2021-I2M-1-067), the Fundamental Research Funds for the Central Universities (3332021091), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT310027).Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.