Rebooting the Adaptive Immune Response in Immunotherapy‐Resistant Lung Adenocarcinoma Using a Supramolecular Albumin

Abstract 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.