免疫检查点阻断（ICB）彻底改变了癌症治疗。然而，仅 ICB 已证明仅对一小部分乳腺癌患者有益处。最近的研究表明，针对 DNA 损伤反应的药物可提高 ICB 的功效并促进细胞质 DNA 积累。然而，最近的临床试验表明这些药物与血液学毒性有关。迫切需要更有效的治疗策略。使用多重免疫组织化学染色对原发性三阴性乳腺癌肿瘤进行胞质单链 DNA (ssDNA) 染色。为了增加胞质 ssDNA，我们对 TREX1 进行了基因沉默。利用小鼠乳腺癌模型评估了肿瘤细胞质 ssDNA 在促进肿瘤免疫原性和抗肿瘤免疫反应中的作用。我们发现肿瘤细胞质 ssDNA 与三阴性乳腺癌患者的肿瘤浸润淋巴细胞相关。 TREX1 缺陷通过 DDX3X 触发不依赖于 STING 的先天免疫反应。 TREX1 缺失导致肿瘤中胞浆 ssDNA 的积累足以大幅提高 ICB 的疗效。我们进一步鉴定了一种胞质 ssDNA 诱导剂 CEP-701，它使乳腺肿瘤对 ICB 敏感，而没有与抑制 DNA 损伤反应相关的毒性。这项工作表明，胞质 ssDNA 积累促进乳腺癌免疫原性，可能是一种提高乳腺癌疗效的新治疗策略。 ICB 毒性最小。© 作者（或其雇主）2023。根据 CC BY-NC 允许重复使用。不得商业再利用。请参阅权利和权限。英国医学杂志出版。

Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, ICB alone has demonstrated only benefit in a small subset of patients with breast cancer. Recent studies have shown that agents targeting DNA damage response improve the efficacy of ICB and promote cytosolic DNA accumulation. However, recent clinical trials have shown that these agents are associated with hematological toxicities. More effective therapeutic strategies are urgently needed.Primary triple negative breast cancer tumors were stained for cytosolic single-stranded DNA (ssDNA) using multiplex immunohistochemical staining. To increase cytosolic ssDNA, we genetically silenced TREX1. The role of tumor cytosolic ssDNA in promoting tumor immunogenicity and antitumor immune response was evaluated using murine breast cancer models.We found the tumorous cytosolic ssDNA is associated with tumor-infiltrating lymphocyte in patients with triple negative breast cancer. TREX1 deficiency triggered a STING-independent innate immune response via DDX3X. Cytosolic ssDNA accumulation in tumors due to TREX1 deletion is sufficient to drastically improve the efficacy of ICB. We further identified a cytosolic ssDNA inducer CEP-701, which sensitized breast tumors to ICB without the toxicities associated with inhibiting DNA damage response.This work demonstrated that cytosolic ssDNA accumulation promotes breast cancer immunogenicity and may be a novel therapeutic strategy to improve the efficacy of ICB with minimal toxicities.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.