Targeted Initiation of Trained Immunity in Tumor-Associated Macrophages with Membrane-Camouflaged Bacillus Calmette-Guérin for Lung Carcinoma Immunotherapy.

Abstract

Inducing trained immunity in macrophages is an increasingly promising strategy for preventing cancer development. However, it has not been investigated whether trained immunity in tumor-associated macrophages (TAMs) can be initiated for antitumor applications. Here, we provide a practical strategy that utilizes the macrophage membrane (M) to camouflage Bacillus Calmette-Guérin (M@BCG), endowing it with the capability to selectively target tumors and efficiently induce trained immunity for TAMs. Using a mouse model of Lewis lung carcinoma, we show that the introduction of macrophage membrane increases BCG's accumulation in orthotopic lung cancer tissues compared with naked BCG. The superior tumor-targeting ability can augment BCG-mediated trained immunity in TAMs, leading to a robust activation of immune responses. Furthermore, macrophage depletion and adoptive transfer of BCG-trained TAM experiments demonstrate that the antitumor activity of M@BCG is dependent on the trained immunity of TAMs. More importantly, intravenous administration of M@BCG can synergistically reinforce the antitumor activity of immune checkpoint blockade without causing systemic toxicity. Taken together, our study demonstrates the successful initiation of trained immunity in TAMs using M@BCG, which exhibits prominent antitumor performance through immune activation.