Immunotherapy has revolutionized the landscape in clinical tumor therapy, although the response rates in "cold" tumors are relatively low owing to the complex tumor microenvironment (TME). Cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway-inducing agents can reprogram the TME; however, their applications remain underutilized. Herein, we engineered a facile manganese-based metal-organic framework (Mn-MOF) encapsulating polyphyllin I (PPI) and coated it with red blood cell (RBC) membranes (RBC@Mn-MOF/PPI) that enhanced the cGAS/STING-mediated antitumor immunity. RBC@Mn-MOF/PPI was engineered by camouflaging it with a biomimetic RBC membrane for prolonged blood circulation and immune escape, which was also extended with TME-sensitive properties for triggering the release of PPI and Mn2+ to remodel the suppressive TME and augment antitumor immune responses. Furthermore, RBC@Mn-MOF/PPI helped transform cold tumors into "hot" ones by activating immune cells, as evidenced via dendritic cell maturation, cytotoxic T lymphocyte infiltration, and natural killer cell recruitment, thereby targeting primary and abscopal tumors and lung metastatic nodules. Therefore, our engineered nanosystem represents a novel strategy to transform immunologically "cold" tumors into "hot" ones by activating the cGAS/STING pathway, thereby addressing the major challenges associated with immunotherapy.
Keywords: cGAS/STING pathway; immunotherapy; manganese-based metal−organic framework; polyphyllin I; tumor microenvironment.