结直肠癌 (CRC) 中的 SMAD4 缺陷与肝转移和高死亡率高度相关，但目前几乎没有有效的精准治疗方法。在这里，我们表明，在临床标本和小鼠模型中，CCR1 粒细胞骨髓源性抑制细胞 (G-MDSC) 分别通过 CCL15/CCR1 和 CCL9/CCR1 轴高度浸润在 SMAD4 缺陷的 CRC 中。肿瘤浸润的 CCR1 -G-MDSC 分泌的过量 TGF-β 会抑制细胞毒性 T 淋巴细胞 (CTL) 的免疫反应，从而促进转移。因此，我们开发了展示 CCR1 和 TGFBR2 分子 (C/T-NV) 的工程化纳米囊泡，以趋化性地靶向由 CCL9/CCR1 轴驱动的肿​​瘤，并通过 TGF-β-TGFBR2 特异性结合捕获 TGF-β。趋化 C/T-NV 通过竞争性响应 CCL9/CCR1 轴抵消 CCR1 -G-MDSC 渗透。 C/T-NVs 诱导的瘤内 TGF-β 耗竭减轻了 CTL 的 TGF-β 抑制的免疫反应。总的来说，C/T-NV 可以减弱 SMAD4 缺陷型 CRC 的肝转移。在进一步的探索中，在 SMAD4 缺陷的 CRC 临床标本中观察到程序性细胞死亡配体 1 (PD-L1) 的高表达。将 C/T-NV 与抗 PD-L1 抗体 (aPD-L1) 组合可诱导三级淋巴结构形成，持续激活 CTL、CXCL13 -CD4 T、CXCR5 -CD20 B 细胞，并增强细胞毒性细胞因子白细胞介素 - 21 和肿瘤周围的IFN-γ，从而根除转移灶。我们的策略引发了多效性抗转移免疫，为 SMAD4 缺陷的 CRC 中纳米囊泡介导的精准免疫治疗铺平了道路。© 2024 作者。

SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1+-granulocytic myeloid-derived suppressor cells (G-MDSCs) are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models, respectively. The excessive TGF-β, secreted by tumor-infiltrated CCR1+-G-MDSCs, suppresses the immune response of cytotoxic T lymphocytes (CTLs), thus facilitating metastasis. Hereby, we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules (C/T-NVs) to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF-β through TGF-β-TGFBR2 specific binding. Chemotactic C/T-NVs counteract CCR1+-G-MDSC infiltration through competitive responding CCL9/CCR1 axis. C/T-NVs-induced intratumoral TGF-β exhaustion alleviates the TGF-β-suppressed immune response of CTLs. Collectively, C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC. In further exploration, high expression of programmed cell death ligand-1 (PD-L1) is observed in clinical specimens of SMAD4-deficient CRC. Combining C/T-NVs with anti-PD-L1 antibody (aPD-L1) induces tertiary lymphoid structure formation with sustained activation of CTLs, CXCL13+-CD4+ T, CXCR5+-CD20+ B cells, and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN-γ around tumors, thus eradicating metastatic foci. Our strategy elicits pleiotropic antimetastatic immunity, paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.© 2024 The Authors.