关键词： ALP, alkaline phosphatise ALT, alanine transaminase AST, aspartate aminotransferase ATP, adenosine triphosphate BUN, blood urea nitrogen CDT, chemodynamic therapy CLSM, confocal laser scanning microscope CREA, creatinine CRT, calreticulin CTLA-4, cytotoxic T-lymphocyte-associated protein 4 CTLs, cytotoxic T lymphocytes Cancer immunotherapy Ce6, Chlorin e6 DAMPs, damage-related molecular patterns DAPI, 2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride DCs, dendritic cells DLS, dynamic light scattering DMPO, dimethyl pyridine N-oxide EDC, 1-ethyl-3-(3ʹ-dimethylaminopropyl) carbodiimide EDS, energy-dispersive spectrometry EPR, enhanced permeability and retention ESR, electron spin resonance FG, FeS-GOx nanodots FGP, FeS-GOx@PTX nanoparticles FITC, fluorescein Isothiocyanate FeCl2·4H2O, iron dichloride tetrahydrate FeS-based cascade bioreactor GOx, glucose oxidase Glu, glucose Glucose oxidase H&E, hematoxylin and eosin H2DCFDA, 2,7-dichlorodihydrofluorescein acetoacetic acid HMGB-1, high mobility group box protein 1 HPF, 2-[6-(4,-hydroxy) phenoxy-3H-xanthene-3-on-9-yl HSA, human serum albumin ICB, immune checkpoint blockade ICD amplifier ICD, immunogenic cell death IFN-γ, interferon-γ MB, methylene blue MCTS, multicellular tumor spheroids MFI, median fluorescence Intensity Metastasis inhibition NHS, N-hydroxy succinimide Na2S, sodium sulfide OH, hydroxyl PBS, phosphate buffer saline PTT, photothermal therapy PTX, paclitaxel ROS, reactive oxygen species SEM, scanning electron microscope Synergistic therapy TAA, tumor-associated antigens TDLN, tumor-draining lymph nodes TEM, transmission microscope TMB, 3,3ʹ,5,5ʹ-tetramathylbenzidine TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labelling Tumor penetration XPS, X-ray photoelectron spectroscopy XRD, X-ray diffraction patterns

来  源：   DOI：10.1016/j.apsb.2021.05.005   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death (ICD) to provoke a robust immune response for metastasis control. Here, a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation, chemodynamic (CDT) and photothermal therapy. Ultrasmall FeS-GOx nanodots were synthesized with glucose oxidase (GOx) as template and induced by paclitaxel (PTX) to form self-assembling FeS-GOx@PTX (FGP) via hydrophobic interaction. After accumulated at tumor sites, FGP disassembles to smaller FeS-GOx for enhanced deep tumor penetration. GOx maintains high enzymatic activity to catalyze glucose with assistant of oxygen to generate hydrogen peroxide (H2O2) as starvation therapy. Fenton reaction involving the regenerated H2O2 in turn produced more hydroxyl radicals for enhanced CDT. Following near-infrared laser at 808 nm, FGPs displayed pronounced tumor inhibition in vitro and in vivo by the combination therapy. The consequent increased exposure to calreticulin amplified ICD and promoted dendritic cells maturation. In combination with anti-CTLA4 checkpoint blockade, FGP can absolutely eliminate primary tumor and avidly inhibit distant tumors due to the enhanced intratumoral infiltration of cytotoxic T lymphocytes. Our work presents a promising strategy for primary tumor and metastasis inhibition.
摘要：
癌症治疗的主要挑战是如何有效消除原发性肿瘤并充分诱导免疫原性细胞死亡（ICD）以激发强大的免疫反应来控制转移。这里,开发了一种自组装的级联生物反应器，以增强肿瘤渗透和饥饿的协同治疗来改善癌症治疗，化学动力学（CDT）和光热疗法。以葡萄糖氧化酶(GOx)为模板合成超小FeS-GOx纳米点,紫杉醇(PTX)通过疏水作用诱导形成自组装FeS-GOx@PTX(FGP)。在肿瘤部位积累后，FGP分解为较小的FeS-GOx，以增强肿瘤的深层渗透。GOx维持高的酶活性以在氧的辅助下催化葡萄糖以产生过氧化氢(H2O2)作为饥饿疗法。涉及再生H2O2的Fenton反应进而产生更多的羟基自由基以增强CDT。跟随808nm的近红外激光，通过联合治疗,FGP在体外和体内显示出显著的肿瘤抑制。随之而来的钙网织蛋白暴露增加了ICD并促进了树突状细胞的成熟。结合抗CTLA4检查点封锁，由于细胞毒性T淋巴细胞的肿瘤内浸润增强，FGP可以绝对消除原发性肿瘤并积极抑制远处肿瘤。我们的工作提出了一种有希望的原发性肿瘤和转移抑制策略。
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