循环肿瘤细胞（CTC）是癌症转移的前体。然而，CTC 在血行传播过程中如何逃避免疫监视仍不清楚。我们通过单细胞 RNA 测序和多种癌症类型血液样本的多重免疫荧光鉴定了 CTC 与血小板的粘附。临床上，CTC-血小板聚集体与肝细胞癌患者的无进展生存期和总生存期显着缩短相关。体外、离体和体内试验表明，直接血小板粘附使癌细胞具有通过上调抑制性检查点 CD155 逃避自然杀伤 (NK) 细胞杀伤的能力，从而促进远处转移。从机制上讲，CD155 受 FAK/JNK/c-Jun 级联以血小板接触依赖性方式转录调节。进一步的竞争测定和细胞毒性实验表明，CTC 上的 CD155 仅通过与免疫受体 TIGIT 结合来抑制 NK 细胞的细胞毒性，而不是通过与 CD155 的另外两种受体 CD96 和 DNAM1 结合来抑制 NK 细胞毒性。中断 CD155-TIGIT 与 TIGIT 抗体的相互作用可恢复 NK 细胞对 CTC 的免疫监视，并显着减弱肿瘤转移。我们的结果表明，CTC 主要通过免疫检查点 CD155-TIGIT 逃避 NK 细胞介导的先天免疫监视，这可能为根除 CTC 提供免疫治疗策略.版权所有 © 2024 美国肝病研究协会。

Circulating tumor cells (CTCs) are precursors of cancer metastasis. However, how CTCs evade immunosurveillance during hematogenous dissemination remains unclear.We identified CTC-platelet adhesions by single-cell RNA sequencing and multiplex immunofluorescence of blood samples from multiple cancer types. Clinically, CTC-platelet aggregates were associated with significantly shorter progression-free survival and overall survival in hepatocellular carcinoma patients. In vitro, ex vivo, and in vivo assays demonstrated direct platelet adhesions gifted cancer cells with an evasive ability from natural killer (NK) cell killing by upregulating inhibitory checkpoint CD155, therefore facilitating distant metastasis. Mechanistically, CD155 was transcriptionally regulated by the FAK/JNK/c-Jun cascade in a platelet contact-dependent manner. Further competition assays and cytotoxicity experiments revealed that CD155 on CTCs inhibited NK cell cytotoxicity only by engaging with immune receptor TIGIT, but not CD96 and DNAM1, another two receptors for CD155. Interrupting the CD155-TIGIT interactions with a TIGIT antibody restored NK cell immunosurveillance on CTCs and markedly attenuated tumor metastasis.Our results demonstrated CTC evasion from NK cell-mediated innate immunosurveillance mainly via immune checkpoint CD155-TIGIT, potentially offering an immunotherapeutic strategy for eradicating CTCs.Copyright © 2024 American Association for the Study of Liver Diseases.