Dual Closed-Loop of Catalyzed Lactate Depletion and Immune Response to Potentiate Photothermal Immunotherapy

Abstract

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.

Acidic and hypoxic tumor microenvironment regulation by CaO2-loaded polydopamine nanoparticles

“…The synthesis of mPDA was carried out according to our previous work [ 28 ], firstly, 500 mg DA and 1000 mg Pluronic F127 were dissolved in 100 mL 50% ethanol under stirring. Then, 2 mL of TMB was added drop by drop into the solution.…”

Lipid–Polymer Hybrid Nanoparticles with Both PD-L1 Knockdown and Mild Photothermal Effect for Tumor Photothermal Immunotherapy

“…Then, DCs, which produce a central effect in the activation and maintenance of antitumor T cell immunity, migrate to lymph nodes and activate naive T cells into effector T cells. , Mature DCs have stronger antigen presentation ability, and their cell surface expresses more costimulatory molecules including CD80 and CD86. CD80 and CD86 are mature markers of DCs . After treatment, tumor drainage lymph nodes were collected to analyze the effect of lip@PSD-siP-mediated mild PTT on the maturation of DCs.…”

“…Photothermal therapy (PTT) is a precise strategy for tumor treatment. It can ablate tumor tissue with the help of external thermal stimulation, characterized by noninvasive, local effect, and simple operation. , In conventional PTT, high temperature (>45 °C) plays the role of tumor ablation, which may lead to normal tissue damage or tumor metastasis and recurrence. , Mild PTT uses a relatively low temperature (42–45 °C) to treat tumor sites, which causes less damage to normal tissues and has the function of inducing immunogenic cell death (ICD). – When tumor cells are experiencing ICD, damage-related molecular patterns (DAMPs) such as high mobility group box 1 (HMGB1) and calreticulin (CRT) will be released from dying tumor cells, promoting the maturation and antigen presentation of dendritic cells (DCs), resulting in activation and tumor infiltration of T cells . Following that, the sensitivity of the tumor to ICB therapy will be increased .…”

Nanomaterials: small particles show huge possibilities for cancer immunotherapy

“…On the one hand, the hypoxic environment of tissues limits the action of LOX, and on the other hand, the oxygen-consuming property aggravates the lactate accumulation in tumor tissues [ 195 , 196 ]. To break the deadly cycle of LOX-catalyzed lactate, Dong et al [ 197 ] loaded Cu 2+ and LOX onto mPDA (mesoporous polydopamine nanoparticles) by ligand and electrostatic adsorption. They then modified the mesoporous surface with PEG to obtain the end product, mCuLP.…”