Metronomic cancer chemotherapy has displayed the potential to ameliorate immunosuppressive tumor microenvironment (TME) and facilitate antitumor immunotherapy, but this strategy requires uninterrupted administration of low-dose chemotherapeutic agents and suffers from rapid drug clearance. Here, we developed a single-dose in situ immune stimulator storage to achieve prolonged retention and sustained release of drugs in tumor parenchyma. Importantly, this storage could initiate immune responses through photothermal therapy (PTT) and simultaneously remodel TME. In detail, the storage framework (NGOPC) with size of ~60 nm, was composed of Ala-Ala-Asn-Cys-Lys modified nano graphene oxide (NGO-PEG-pep) and 2-cyano-6-aminobenzothiazole modified NGO (NGO-PEG-CABT), and could sufficiently penetrate into deep tumor region. Once NGOPC arrived at the core field, legumain overexpressing in TME could trigger click cycloaddition reaction of NGO-PEG-pep with NGO-PEG-CABT to form network, leading to aggregation and augmented retention in tumor. Additionally, paclitaxel (PTX) that can block immunologic escape was loaded in NGOPC (NGOPC@PTX), which synergistically worked with PTT-generated antitumor immunity. We found that NGOPC@PTX possessed the superior ability to accumulate in tumor and generate antitumor immunological efficacy by improving immune factors: induction of HSP70-mediated immunogenic cell death, reduction of regulatory T cells, and activation of cytotoxic T lymphocyte. This in situ storage, which exhibited excellent tumor growth inhibition effect and prolonged lifespan in combination with PTT, displays the potential for intensified cancer immunotherapy.

中文翻译：

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单剂量原位储存可通过组合策略增强抗癌功​​效。

节律癌化学疗法已显示出改善免疫抑制肿瘤微环境（TME）和促进抗肿瘤免疫疗法的潜力，但是这种策略要求不间断给予低剂量化疗药物，而且药物清除迅速。在这里，我们开发了一种单剂量原位免疫刺激剂储存剂，以实现在肿瘤实质中药物的长期保留和持续释放。重要的是，这种储存可以通过光热疗法（PTT）引发免疫反应，并同时重塑TME。详细而言，大小约为60 nm的存储框架（NGOPC）由Ala-Ala-Asn-Cys-Lys修饰的纳米石墨烯氧化物（NGO-PEG-pep）和2-氰基-6-氨基苯并噻唑修饰的NGO（ NGO-PEG-CABT），并且可以充分渗透到深部肿瘤区域。一旦NGOPC进入核心领域，TME中的豆科菌素过表达可能会触发NGO-PEG-pep与NGO-PEG-CABT的点击环加成反应形成网络，从而导致聚集和增加在肿瘤中的保留。另外，可以阻止免疫逃逸的紫杉醇（PTX）被装载到NGOPC（NGOPC @ PTX）中，它与PTT产生的抗肿瘤免疫作用协同作用。我们发现NGOPC @ PTX具有通过改善免疫因素而在肿瘤中蓄积并产生抗肿瘤免疫学功效的卓越能力：诱导HSP70介导的免疫原性细胞死亡，减少调节性T细胞和激活细胞毒性T淋巴细胞。与PTT结合使用时，这种原位储存具有优异的肿瘤生长抑制作用和延长的寿命，显示出加强癌症免疫疗法的潜力。豆蔻因在TME中过表达可能会触发NGO-PEG-pep与NGO-PEG-CABT的点击环加成反应形成网络，从而导致肿瘤聚集和增强的保留。另外，可以阻止免疫逃逸的紫杉醇（PTX）被装载到NGOPC（NGOPC @ PTX）中，它与PTT产生的抗肿瘤免疫作用协同作用。我们发现NGOPC @ PTX具有通过改善免疫因素而在肿瘤中积累和产生抗肿瘤免疫学功效的卓越能力：诱导HSP70介导的免疫原性细胞死亡，减少调节性T细胞和激活细胞毒性T淋巴细胞。与PTT结合使用时，这种原位储存具有优异的肿瘤生长抑制作用和延长的寿命，显示出加强癌症免疫疗法的潜力。豆蔻因在TME中过表达可能会触发NGO-PEG-pep与NGO-PEG-CABT的点击环加成反应形成网络，从而导致肿瘤聚集和增强的保留。另外，可以阻止免疫逃逸的紫杉醇（PTX）被装载到NGOPC（NGOPC @ PTX）中，它与PTT产生的抗肿瘤免疫作用协同作用。我们发现NGOPC @ PTX具有通过改善免疫因素而在肿瘤中蓄积并产生抗肿瘤免疫学功效的卓越能力：诱导HSP70介导的免疫原性细胞死亡，减少调节性T细胞和激活细胞毒性T淋巴细胞。与PTT结合使用时，这种原位储存具有优异的肿瘤生长抑制作用和延长的寿命，显示出加强癌症免疫疗法的潜力。