免疫逃避是肿瘤免疫治疗中的一个主要挑战。Pleckstrin-2（PLEK2）在肿瘤进展中起着关键作用，但其在胃癌（GC）中的免疫逃避中的作用尚未被表征。使用RNA测序探索了一种对天然杀伤细胞（NK细胞）的抗肿瘤效应具有耐药性的GC细胞系中的差异表达基因。通过流式细胞术（FCM）检测细胞凋亡以及IFN-γ和TNF-α的表达。通过Western blotting和免疫组化（IHC）检测PLEK2的表达。在对NK细胞杀伤具有抗肿瘤效应的MGC803R细胞中，PLEK2表达上调。PLEK2敲除增加了GC细胞对NK细胞杀伤的敏感性。PLEK2的表达与体外和体内的MICA表达呈负相关，与MT1-MMP表达呈正相关。PLEK2通过PI3K-AKT途径促进Sp1磷酸化，从而上调MT1-MMP表达，最终导致MICA的脱落。在小鼠异种移植模型中，PLEK2敲除抑制了GC细胞的腹膜播散，并促进了NK细胞的浸润。总之，PLEK2通过促进MICA的脱落抑制了NK细胞的免疫监视，成为GC潜在的治疗靶点。版权所有©2023 Elsevier B.V.出版。

Immune escape is a major challenge in tumour immunotherapy. Pleckstrin-2(PLEK2) plays a critical role in tumour progression, but its role in immune escape in gastric cancer (GC) remains uncharacterized. RNA sequencing was used to explore the differentially expressed genes in a GC cell line that was resistant to the antitumor effect of Natural killer (NK) cells. Apoptosis and the expression of IFN-γ and TNF-α were detected by flow cytometry (FCM). PLEK2 expression was examined by Western blotting and immunohistochemistry (IHC). PLEK2 was upregulated in MGC803R cells that were resistant to the antitumor effect of NK cells. PLEK2 knockout increased the sensitivity of GC cells to NK cell killing. PLEK2 expression was negatively correlated with MICA and positively correlated with MT1-MMP expression both in vitro and in vivo. PLEK2 promoted Sp1 phosphorylation through the PI3K-AKT pathway, thereby upregulating MT1-MMP expression, which ultimately led to MICA shedding. In mouse xenograft models, PLEK2 knockout inhibited intraperitoneal metastasis of GC cells and promoted NK cell infiltration. In summary, PLEK2 suppressed NK cell immune surveillance by promoting MICA shedding, which serves as a potential therapeutic target for GC.Copyright © 2023. Published by Elsevier B.V.