尽管免疫检查点抑制剂（ICB）的出现显着延长了一些肺腺癌（LUAD）患者的预期寿命，但其实施和长期有效性却因日益严重的获得性耐药问题而受到阻碍。在此，免疫治疗耐药性 LUAD 患者的生物信息学分析和抗 PD1 耐药小鼠模型的系统分析再次验证了耐药相关的 Wnt/β-catenin 通路为 ICB 致敏提供了一条有希望的途径。因此，采用白蛋白和鼠尾草酸 (CA)（一种 Wnt 抑制剂）之间温和且方便的自组装，开发出一种称为 ABCA 的超分子白蛋白，作为 ICB 的再激活剂。正如预期的那样，ABCA 在体外有效抑制 Wnt/β-catenin 级联反应，显着抑制细胞增殖，同时促进细胞凋亡。最值得注意的是，ABCA 通过重振 T 淋巴细胞介导的适应性免疫反应，恢复了 Anti-PD1 在免疫治疗耐药 LUAD 原位同种异体移植小鼠模型中的抗癌功效。此外，ABCA 在治疗和高剂量毒性测试中表现出最小的不良反应，凸显了其临床转化的巨大潜力。总的来说，目前的工作有可能为针对耐药性的优化免疫疗法的进展提供创新视角，同时也为将 Wnt 抑制剂转化为免疫治疗药物进行临床应用提供了一条有前途的途径。© 2024 作者。小号由 Wiley‐VCH GmbH 出版。

Despite the availability of immune checkpoint inhibitors (ICBs) significantly prolonging the life expectancy of some lung adenocarcinoma (LUAD) patients, their implementation and long-term effectiveness are hampered by the growing issue of acquired resistance. Herein, the bioinformatics analysis of immunotherapy-resistant LUAD patients and the system analysis of Anti-PD1-resistant mice models once again validate that the resistance-associated Wnt/β-catenin pathway offers a promising avenue for ICB sensitization. Consequently, a mild and convenient self-assembly between albumin and carnosic acid (CA), a Wnt inhibitor is employed, to develop a supramolecular albumin known as ABCA, serving as a reactivator for ICB. As anticipated, ABCA effectively suppress the Wnt/β-catenin cascade in vitro and leads to significant inhibition of cell proliferation while promoting apoptosis. Most notably, ABCA restores the anticancer efficacy of Anti-PD1 in immunotherapy-resistant LUAD orthotopic allografting mice models by reinvigorating the adaptive immune response mediated by T lymphocytes. Furthermore, ABCA exhibits minimal adverse effects during treatment and high-dose toxicity tests, underscoring its excellent potential for clinical translation. Collectively, the present work possesses the potential to provide innovative perspectives on the advancement of optimized immunotherapies targeting drug resistance, while also presenting a promising avenue for translating Wnt inhibitors into immunotherapeutic drugs for their clinical application.© 2024 The Author(s). Small published by Wiley‐VCH GmbH.