Immunosuppressive tumor microenvironments (TMEs) create tremendous obstacles for an effective cancer therapy. Herein, we developed a melittin-RADA32 hybrid peptide hydrogel loaded with doxorubicin (DOX) for a potent chemoimmunotherapy against melanoma through the active regulation of TMEs. The formed melittin-RADA32-DOX (MRD) hydrogel has an interweaving nanofiber structure and exhibits excellent biocompatibility, controlled drug release properties both in vitro and in vivo, and an enhanced killing effect to melanoma cells. A single-dose injection of MRD hydrogel retarded the growth of primary melanoma tumors by more than 95% due to loaded melittin and DOX, with concomitant recruitment of activated natural killer cells in the tumors. Furthermore, MRD hydrogel can activate dendritic cells of draining lymph nodes, specifically deplete M2-like tumor-associated macrophages (TAMs), and produce active, cytotoxic T cells to further defend the cells against remaining tumors, providing potent anticancer efficacy against subcutaneous and metastatic tumors in vivo. Multidose injection of MRD hydrogel eliminated 50% of the primary tumors and provided a strong immunological memory effect against tumor rechallenge after eradication of the initial tumors. Owing to its abilities to perform controlled drug release, regulate innate immune cells, deplete M2-like TAMs, direct anticancer and immune-stimulating capabilities, and reshape immunosuppressive TMEs, MRD hydrogel may serve as a powerful tool for anticancer applications.
Keywords: biomaterials; chemoimmunotherapy; cytotoxic T cells; hydrogel; macrophage depletion; melanoma treatment; tumor microenvironment.