Circulating tumor cells (CTCs) are precursors of distant metastasis in a subset of cancer patients. A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the foundation for therapeutic prevention of cancer metastasis. It remains elusive how CTCs evade immune surveillance and elimination by immune cells. In this study, we unequivocally identified a subpopulation of CTCs shielded with extracellular vesicle (EVs)-derived CD45 (termed as CD45⁺ CTCs) that resisted T cell attack. A higher percentage of CD45⁺ CTCs was found to be closely correlated with higher incidence of metastasis and worse prognosis in cancer patients. Moreover, CD45⁺ tumor cells orchestrated an immunosuppressive milieu and CD45⁺ CTCs exhibited remarkably stronger metastatic potential than CD45⁻ CTCs in vivo. Mechanistically, CD45 expressing on tumor surfaces was shown to form intercellular CD45-CD45 homophilic interactions with CD45 on T cells, thereby preventing CD45 exclusion from TCR-pMHC synapse and leading to diminished TCR signaling transduction and suppressed immune response. Together, these results pointed to an underappreciated capability of EVs-derived CD45-dressed CTCs in immune evasion and metastasis, providing a rationale for targeting EVs-derived CD45 internalization by CTCs to prevent cancer metastasis.

循环肿瘤细胞（CTC）是一部分癌症患者远处转移的前体。更好地了解 CTC 的异质性以及这些 CTC 在血行传播过程中如何存活，可以为癌症转移的治疗预防奠定基础。 CTC 如何逃避免疫监视和免疫细胞的消除仍然难以捉摸。在这项研究中，我们明确鉴定了一个 CTC 亚群，其受到细胞外囊泡 (EV) 衍生的 CD45（称为 CD45 ⁺ CTC）的保护，可抵抗 T 细胞攻击。研究发现，较高比例的CD45 ⁺ CTC与癌症患者较高的转移发生率和较差的预后密切相关。此外，CD45 ⁺肿瘤细胞精心策划了免疫抑制环境，并且 CD45 ⁺ CTC在体内表现出比 CD45 ^- CTC明显更强的转移潜力。从机制上讲，肿瘤表面表达的 CD45 与 T 细胞上的 CD45 形成细胞间 CD45-CD45 同亲相互作用，从而防止 CD45 从 TCR-pMHC 突触中排除，导致 TCR 信号传导减弱并抑制免疫反应。总之，这些结果表明，EV 衍生的 CD45 修饰的 CTC 在免疫逃避和转移方面的能力未被充分认识，这为 CTC 靶向 EV 衍生的 CD45 内化以预防癌症转移提供了理论依据。