Construction of a cascade nanosystem to implement indirect and direct cell modulation for tumor microenvironment immunostimulation

Reprogramming of tumor associated macrophages (TAMs) from M2 to M1 phenotype is becoming a feasible strategy for tumor immunotherapy, however, its efficacy is potentially constrained by the acellular components of immunosuppressive tumor microenvironment (TME). Herein, hollow MnO2 (HMnO2) nanoparticles were loaded with autophagy inhibitor chloroquine (CQ), carried both lactate oxidase (LOX) and glucose oxidase (GOX) on their surface, and further were camouflaged with tumor cell membrane, forming the final mCMLG nanoparticles for TME immunostimulation. After intravenous injection, mCMLG nanoparticles effectively accumulated in the tumor area and were taken up by tumor cells. Under the acidic conditions, MnO2 reacted with endogenous hydrogen peroxide (H2O2) to generate O2 and Mn2+, resulting in the exposure of LOX and GOX as well as the release of CQ. The exposed enzymes reduced the level of lactate (a predominant acellular component), alleviating the inhibition on TAM reprogramming; hydroxyl radical (·OH) generated by Fenton-like reaction of Mn2+ could directly promote this reprogramming, thus effectively facilitating the reprogramming of TME from immunosuppressive to immunostimulatory. Moreover, ·OH also induced chemodynamic therapy (CDT) effect against tumor cells, which was further amplified by CQ. This study corroborates that mCMLG nanoparticles can effectively inhibit tumor growth through the enhanced immunotherapy and CDT.