Multifunctional Redox-Responsive Nanoplatform with Dual Activation of Macrophages and T Cells for Antitumor Immunotherapy.

High expression of programmed death ligand 1 (PD-L1) and strong immune evasion ability of the tumor microenvironment (TME) are maintained through mutual regulation between different immune and stromal cells, which causes obstructions for cancer immunotherapy, especially immunosuppressive M2-like phenotype tumor-associated macrophages (TAMs). Repolarization of TAMs to the M1-like phenotype could secrete proinflammatory cytokines and reverse the immunosuppressive state of the TME. However, we found that reactive oxygen species (ROS) generated by repolarized TAMs could be a double-edged sword: ROS cause a stronger suppressive effect on CD8 T cells through an increased proportion of apoptotic regulatory T (Treg) cells. Thus, simply repolarizing TAMs while ignoring the suppressed function of T cells is insufficient for generating adequate antitumor immunity. Accordingly, we engineered multifunctional redox-responsive nanoplatform NPs (M+C+siPD-L1) with Toll-like receptor agonist (M), catalase (C), and siPD-L1 encased for coregulation of both TAMs and T cells to maximize cancer immunotherapy. Our results demonstrated that NPs (M+C+siPD-L1) showed superior biocompatibility and intratumor accumulation. For in vitro experiments, NPs (M+C+siPD-L1) simultaneously repolarized TAMs to the M1-like phenotype, hydrolyzed extra ROS, knocked down the expression of PD-L1 on tumor cells, and rescued the function of CD8 T cells suppressed by Treg cells. In both orthotopic Hepa1-6 and 4T1 tumor-bearing mouse models, NPs (M+C+siPD-L1) could effectively evoke active systemic antitumor immunity and inhibit tumor growth. The combination of repolarizing TAMs, hydrolyzing extra ROS, and knocking down the expression of PD-L1 proves to be a synergistic approach in cancer immunotherapy.