Engineered Bacterial Biomimetic Vesicles Reprogram Tumor-Associated Macrophages and Remodel Tumor Microenvironment to Promote Innate and Adaptive Antitumor Immune Responses

作者：Peng Zheng, Jinrong He, Yuting Fu, Ying Yang, Shuqin Li, Biao Duan, Ying Yang, Yongmao Hu, Zhongqian Yang, Mengzhen Wang, Qingwen Liu, Xiao Zheng, Liangqun Hua, Weiran Li, Duo Li, Yiting Ding, Yang Xu, Hongmei Bai, Qiong Long, Weiwei Huang, Yanbing Ma · 发表于：ACS Nano · 年份：2024 · DOI：10.1021/acsnano.3c06987 · 被引用次数：62 · 研究领域：Immune cells in cancer、Nanoplatforms for cancer theranostics、Phagocytosis and Immune Regulation

Tumor-associated macrophages (TAMs) are among the most abundant infiltrating leukocytes in the tumor microenvironment (TME). Reprogramming TAMs from protumor M2 to antitumor M1 phenotype is a promising strategy for remodeling the TME and promoting antitumor immunity; however, the development of an efficient strategy remains challenging. Here, a genetically modified bacterial biomimetic vesicle (BBV) with IFN-γ exposed on the surface in a nanoassembling membrane pore structure was constructed. The engineered IFN-γ BBV featured a nanoscale structure of protein and lipid vesicle, the existence of rich pattern-associated molecular patterns (PAMPs), and the costimulation of introduced IFN-γ molecules. In vitro, IFN-γ BBV reprogrammed M2 macrophages to M1, possibly through NF-κB and JAK-STAT signaling pathways, releasing nitric oxide (NO) and inflammatory cytokines IL-1β, IL-6, and TNF-α and increasing the expression of IL-12 and iNOS. In tumor-bearing mice, IFN-γ BBV demonstrated a targeted enrichment in tumors and successfully reprogrammed TAMs into the M1 phenotype; notably, the response of antigen-specific cytotoxic T lymphocyte (CTL) in TME was promoted while the immunosuppressive myeloid-derived suppressor cell (MDSC) was suppressed. The tumor growth was found to be significantly inhibited in both a TC-1 tumor and a CT26 tumor. It was indicated that the antitumor effects of IFN-γ BBV were macrophage-dependent. Further, the modulation of TME by IFN-γ BBV produced synergistic e...