Apatinib已被证明可在临床上增强晚期胃癌（GC）抗PD-1免疫疗法的效果。然而，GC免疫抑制的复杂性仍然是精准免疫疗法面临的挑战。在这里，我们对34,182个单个来自人源化小鼠模型的GC患者来源的异种移植细胞进行了转录组分析，这些患者接受了车辆、尼伏普、或尼伏普加阿帕替尼的治疗。值得注意的是，在细胞周期恶性上皮中过量表达的CXCL5，由抗PD-1免疫疗法引起并被联合阿帕替尼治疗阻断，被发现是肿瘤相关中性粒细胞（TAN）通过CXCL5 / CXCR2轴招募到肿瘤微环境中的关键驱动程序。我们进一步表明，原癌TAN签名与抗PD-1免疫治疗相关的进展性疾病和不良肿瘤预后相关。在细胞来源的异种移植模型中的分子和功能分析证实了靶向CXCL5 / CXCR2轴在抗PD-1免疫疗法期间具有正的体内治疗效果。总的来说，我们的研究阐明了抗PD-1免疫疗法中的GC免疫抑制局面，并强调了克服检查点免疫疗法抵抗的潜在目标。版权©2023 The Author(s). Elsevier Inc.保留所有权利。

Apatinib has been shown to clinically enhance anti-PD-1 immunotherapy for advanced gastric cancer (GC). However, the complexity of GC immunosuppression remains a challenge for precision immunotherapy. Here, we profile the transcriptomes of 34,182 single cells from GC patient-derived xenografts of humanized mouse models treated with vehicle, nivolumab, or nivolumab plus apatinib. Notably, excessive expression of CXCL5 in the CellCycle malignant epithelium, induced by anti-PD-1 immunotherapy and blocked by combined apatinib treatment, is found to be a key driver of tumor-associated neutrophil (TAN) recruitment in the tumor microenvironment through the CXCL5/CXCR2 axis. We further show that the protumor TAN signature is associated with anti-PD-1 immunotherapy-related progressive disease and poor cancer prognosis. Molecular and functional analyses in cell-derived xenograft models confirm the positive in vivo therapeutic effect of targeting the CXCL5/CXCR2 axis during anti-PD-1 immunotherapy. Altogether, our study elucidates the GC immunosuppressive landscape in anti-PD-1 immunotherapy and highlights potential targets for overcoming checkpoint immunotherapy resistance.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.