癌症免疫疗法旨在释放免疫系统对抗癌细胞的潜力，持续缓解对免疫检查点抑制剂 (ICIs) 敏感的肿瘤。虽然 ICI 在胃癌 (GC) 试验中很有希望，但在腹膜播散的情况下其疗效会减弱。我们的目标是确定策略，以增强 ICI 治疗的影响，特别是针对涉及 GC 腹膜播散的病例。使用 YTN16 腹膜播散肿瘤模型评估单独或联合抗 PD1、CTLA4 治疗的治疗效果。收集腹膜和腹膜渗出液细胞用于后续分析。通过免疫组织化学染色、流式细胞术和大量 RNA 序列分析来评估肿瘤微环境 (TME)。基于通路分析结果引入了Janus激酶抑制剂（JAKi）。抗PD1和抗CTLA4联合治疗（双ICI治疗）在某些小鼠中显示出治疗功效，主要由CD8  T细胞介导。然而，在对双重 ICI 治疗有抵抗力的小鼠中，即使有 CD8  T 细胞浸润，大多数 T 细胞也表现出衰竭表型。值得注意的是，与未治疗组相比，耐药肿瘤表现出 Janus 激酶信号转导子和转录激活子 (JAK-STAT) 通路的异常激活，并观察到 ​​TME 中巨噬细胞、中性粒细胞和 Tregs 的浸润。同时给予JAKi可挽救CD8  T细胞功能并重塑免疫抑制TME，从而增强双重ICI治疗的疗效。双重ICI治疗通过增加肿瘤特异性CD8  T细胞浸润以及添加JAKi来发挥抗肿瘤作用通过重塑免疫抑制性 TME 进一步提高 ICI 抵抗力。© 2024。作者。

Cancer immunotherapy aims to unleash the immune system's potential against cancer cells, providing sustained relief for tumors responsive to immune checkpoint inhibitors (ICIs). While promising in gastric cancer (GC) trials, the efficacy of ICIs diminishes in the context of peritoneal dissemination. Our objective is to identify strategies to enhance the impact of ICI treatment specifically for cases involving peritoneal dissemination in GC.The therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination was assessed using the YTN16 peritoneal dissemination tumor model. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A Janus kinase inhibitor (JAKi) was introduced based on the pathway analysis results.Anti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8 + T cells. However, in mice resistant to dual ICI treatment, even with CD8 + T cell infiltration, most of the T cells exhibited an exhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8 + T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment.Dual ICI treatment exerts its anti-tumor effects by increasing tumor-specific CD8 + T cell infiltration, and the addition of JAKi further improves ICI resistance by reshaping the immunosuppressive TME.© 2024. The Author(s).