Development of melittin-based anti-cancer drug for targeting tumor-associated macrophages

Abstract Tumor-associated macrophages (TAMs) are the major component of tumor infiltrating immune cells. Macrophages are broadly categorized as M1 or M2 types and TAMs have been known to express M2-like phenotype. TAMs promote tumor progression and contribute to resistant to chemotherapies. Therefore, M2-like TAMs are potential targets for the treatment of cancers. In this study, we targeted M2-like TAMs using a hybrid peptide MEL-dKLA composed of melittin (MEL) peptide, which binds preferentially to M2-like TAMs and d-KLAKLAKKLAKLAK (dKLA) peptide, which induces apoptotic cell death after cell membrane penetration. We showed that the MEL-dKLA induced selective cell death of M2 macrophages by disrupting mitochondrial membrane in vitro while MEL did not show the correlation with mitochondrial apoptosis. We also showed that MEL-dKLA selectively targeted the M2-like TAMs without affecting other leukocytes such as T cells and dendritic cells in vivo. It resulted in the inhibition of tumor growth rate and tumor weight, and angiogenesis in vivo. Importantly, although both MEL and MEL-dKLA reduced the CD206+ M2-like TAMs in the tumor, only MEL-dKLA induced the apoptosis of CD206+ M2-like TAMs whereas the MEL did not show the cell death. Taken together, our study describes MEL-dKLA can be used as the promising therapeutic agent for targeting M2-like TAMs.