免疫检查点抑制剂在癌症患者中产生了令人鼓舞的结果。然而，大多数β-连环蛋白突变的肿瘤被描述为缺乏免疫浸润并对免疫治疗具有抵抗力。致癌β-连环蛋白影响免疫监视的机制仍不清楚。在此，我们强调了β-连环蛋白参与外泌体途径的调节，进而参与肝细胞癌（HCC）的免疫/癌细胞通讯。我们发现，在肝癌细胞系和 HCC 患者样本中，突变的 ß-catenin 会抑制 SDC4 和 RAB27A（外泌体生物发生中的两个主要参与者）的表达。使用纳米颗粒跟踪分析和活细胞成像，我们进一步证明激活的β-连环蛋白抑制外泌体释放。然后，我们在 3D 球体模型中证明，β-连环蛋白的激活通过外泌体分泌缺陷促进免疫细胞浸润的减少。总而言之，我们的结果提供了第一个证据，证明致癌β-连环蛋白在外泌体生物发生中发挥关键作用。我们的研究为 ß-catenin 突变对肿瘤微环境重塑的影响提供了新的见解，这可能导致开发增强免疫治疗反应的新策略。© 2024，Dantzer 等人。

Immune checkpoint inhibitors have produced encouraging results in cancer patients. However, the majority of ß-catenin-mutated tumors have been described as lacking immune infiltrates and resistant to immunotherapy. The mechanisms by which oncogenic ß-catenin affects immune surveillance remain unclear. Herein, we highlighted the involvement of ß-catenin in the regulation of the exosomal pathway and, by extension, in immune/cancer cell communication in hepatocellular carcinoma (HCC). We showed that mutated ß-catenin represses expression of SDC4 and RAB27A, two main actors in exosome biogenesis, in both liver cancer cell lines and HCC patient samples. Using nanoparticle tracking analysis and live-cell imaging, we further demonstrated that activated ß-catenin represses exosome release. Then, we demonstrated in 3D spheroid models that activation of β-catenin promotes a decrease in immune cell infiltration through a defect in exosome secretion. Taken together, our results provide the first evidence that oncogenic ß-catenin plays a key role in exosome biogenesis. Our study gives new insight into the impact of ß-catenin mutations on tumor microenvironment remodeling, which could lead to the development of new strategies to enhance immunotherapeutic response.© 2024, Dantzer et al.