In situ self-assembled peptide enables effective cancer immunotherapy by blockage of CD47

Abstract

Treatment of late-stage lung cancer has witnessed limited advances. In contrast to the tremendous efforts toward improving adaptive immunity, approaches to modulating innate immunity are relatively immature. As important innate immune cells, tumor-associated macrophages (TAMs) account for a substantial fraction of tumor-infiltrating lymphocytes, which not only reverses the immune-suppressive tumor microenvironment but also facilitates an adaptive immune response. In this study, we developed a tumor-specific MMP-2-responsive CD47 blockage (TMCB) strategy to enable effective cancer immunotherapy. Briefly, the matrix metalloproteinase-2 (MMP-2)-responsive self-assembly peptide specifically recognizes CD47, which is highly expressed in lung tumor cells. Second, the MMP-2-responsive self-assembly peptide is efficiently cleaved by MMP-2, which is overexpressed in the tumor microenvironment. Finally, the generated residual peptide naturally self-assembles into peptide-based nanofibers. The in situ constructed nanofibers inhibit the canonical CD47 “Do not eat me” signal expressed on tumor cells to promote phagocytosis of tumor cells by macrophages, which further induces effective antigen presentation and initiates T cell-mediated adaptive immune responses to inhibit tumor growth. Thus, we described a peptide-based TMCB strategy that induces both innate and adaptive immune systems to inhibit tumor growth.