Exosome-guided direct reprogramming of tumor-associated macrophages from protumorigenic to antitumorigenic to fight cancer

Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance.In particular,tumor-associated macrophages(TAMs),as the predominant infiltrated immune cells in a tumor,play a pivotal role in regulating the immunosuppressive tumor microenvironment.As a potential therapeutic strategy to counteract TAMs,here we explore an exosome-guided in situ direct reprogramming of tumor-supportive M2-polarized TAMs into tumor-attacking M1-type macrophages.Exosomes derived from M1-type macrophages(M1-Exo)promote a phenotypic switch from anti-inflammatory M2-like TAMs toward pro-inflammatory M1-type macrophages with high conversion efficiency.Reprogrammed M1 macrophages possessing protein-expression profiles similar to those of classically activated M1 macrophages display significantly increased phagocytic function and robust cross-presentation ability,potentiating antitumor immunity surrounding the tumor.Strikingly,these M1-Exo also lead to the conversion of human patient-derived TAMs into M1-like macrophages that highly express MHC class II,offering the clinical potential of autologous and allogeneic exosome-guided direct TAM reprogramming for arming macrophages to join the fight against cancer.