Exosome-guided direct reprogramming of tumor-associated macrophages from protumorigenic to antitumorigenic to fight cancer
Hyo‐Suk Kim, Hyun‐Ju Park, Hyo Won Chang, Ji Hyun Back, Su Jin Lee, Yae Eun Park, Eun Hye Kim, Yeonsun Hong, Gijung Kwak, Ick Chan Kwon, Ji Eun Lee, Yoon Se Lee, Sang Yoon Kim, Sang Yoon Kim, Yoosoo Yang, Sun Hwa Kim, Sun Hwa Kim
Abstract
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.