Targeted Initiation\nof Trained Immunity in Tumor-Associated\nMacrophages with Membrane-Camouflaged Bacillus Calmette-Guerin\nfor Lung Carcinoma Immunotherapy

Inducing trained immunity in macrophages is an increasingly\npromising\nstrategy for preventing cancer development. However, it has not been\ninvestigated whether trained immunity in tumor-associated macrophages\n(TAMs) can be initiated for antitumor applications. Here, we provide\na practical strategy that utilizes the macrophage membrane (M) to\ncamouflage Bacillus Calmette-Guérin (M@BCG), endowing it with\nthe capability to selectively target tumors and efficiently induce\ntrained immunity for TAMs. Using a mouse model of Lewis lung carcinoma,\nwe show that the introduction of macrophage membrane increases BCG’s\naccumulation in orthotopic lung cancer tissues compared with naked\nBCG. The superior tumor-targeting ability can augment BCG-mediated\ntrained immunity in TAMs, leading to a robust activation of immune\nresponses. Furthermore, macrophage depletion and adoptive transfer\nof BCG-trained TAM experiments demonstrate that the antitumor activity\nof M@BCG is dependent on the trained immunity of TAMs. More importantly,\nintravenous administration of M@BCG can synergistically reinforce\nthe antitumor activity of immune checkpoint blockade without causing\nsystemic toxicity. Taken together, our study demonstrates the successful\ninitiation of trained immunity in TAMs using M@BCG, which exhibits\nprominent antitumor performance through immune activation.