Lactate accumulation in the solid tumor is highly relevant to the immunosuppressive tumor microenvironment (TME). Targeting lactate metabolism significantly enhances the efficacy of immunotherapy. However, lactate depletion by lactate oxidase (LOX) consumes oxygen and results in the aggravated hypoxia situation, counteracting the benefit of lactate depletion. Beyond the TME regulation, it is necessary to initiate the effective immunity cycle for therapeutic purposes. In this fashion, dual close-loop of catalyzed lactate depletion and immune response by a rational material design are established to address this issue. Here, we constructed PEG-modified mesoporous polydopamine nanoparticles with Cu2+ chelation and LOX encapsulation (denoted as mCuLP). After mCuLP nanosystems targeting into the tumor sites, released LOX consumes lactate to H2O2. Subsequently, the produced H2O2 is further catalyzed by Cu2+-chelated mPDA to produce oxygen, supplying the oxygen source for the closed-loop of lactate depletion. Meanwhile, the mild PTT caused by the photothermal mPDA induces ICD of tumor cells to promote DC maturation and then T lymphocyte infiltration to kill tumor cells, which forms another closed-loop for cancer immunity. Therefore, this dual closed-loop strategy of mCuLP nanosystems effectively inhibits tumor growth, providing a promising treatment modality to cancer immunotherapy.
Keywords: closed-loop; immunosuppressive tumor microenvironment; lactate; mesoporous polydopamine; photothermal immunotherapy.