高级别严重卵巢癌（HGSOC）是一种侵袭性恶性肿瘤，目前的免疫疗法仍然难以治愈。虽然晚期疾病已得到广泛研究，但促进 HGSOC 早期免疫逃逸的细胞和分子机制在很大程度上仍未得到探索。在这里，我们报告原发性 HGSO 肿瘤通过激活内质网 (ER) 应激传感器 IRE1α 来编程中性粒细胞抑制 T 细胞抗肿瘤功能。我们发现，与非肿瘤部位的中性粒细胞相比，肿瘤内的中性粒细胞表现出内质网应激反应标记物的过度激活。中性粒细胞中 IRE1α 的选择性缺失可延缓原发性卵巢肿瘤的生长，并通过实现早期 T 细胞介导的肿瘤控制来延长 HGSOC 小鼠的生存期。值得注意的是，中性粒细胞中 IRE1α 的缺失使荷瘤小鼠对 PD-1 阻断更加敏感，从而诱导 HGSOC 消退并在 50% 的接受治疗的宿主中实现长期存活。因此，中性粒细胞固有的 IRE1α 促进 HGSOC 中的早期适应性免疫逃逸，并且针对该 ER 应激传感器可用于释放内源性和免疫治疗引发的免疫，从而控制转移性疾病。© 2024 作者。经泰勒许可出版

High-grade serious ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here, we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ~ 50% of the treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.