免疫检查点阻断（ICB）疗法尽管在临床突破方面取得了显著进展，但由于"冷"肿瘤中免疫应答不足而受到限制。基于纳米酶的抗肿瘤催化与肿瘤微环境（TME）中精确的免疫激活相关联。本研究提出了一种级联增强的纳米免疫调节剂（CMZM），它具有多酶样活性，包括超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、过氧化物酶（POD）和谷胱甘肽氧化酶（GSHOx），在酸性和丰富的谷胱甘肽（GSH）TME中解离。该纳米免疫调节剂通过多酶样活性不仅可以产生氧气以缓解缺氧和促进M2向M1巨噬细胞的极化，而且可以产生ROS（•OH和1 O2）并清除TME中的谷胱甘肽以暴露坏死的细胞碎片，并通过引发树突细胞成熟和细胞毒性T淋巴细胞在肿瘤中的浸润来逆转免疫抑制性TME。因此，通过与α-PD-L1阻断抗体的协同作用，对原发和远处肿瘤都实现了抑制效果。该级联多酶基纳米平台通过修正免疫抑制性TME为高效的ICB免疫疗法提供了智能策略。本文受版权保护，版权所有。

Despite its remarkable clinical breakthroughs, immune checkpoint blockade (ICB) therapy remains limited by the insufficient immune response in the "cold" tumor. Nanozyme-based antitumor catalysis is associated with precise immune activation in the tumor microenvironment (TME). In this study, a cascade-augmented nanoimmunomodulator (CMZM) with multienzyme-like activities, which includes superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione oxidase (GSHOx), that dissociates under an acidic and abundant GSH TME, is proposed for multimodal imaging-guided chemodynamic therapy (CDT)/photodynamic therapy (PDT) enhanced immunotherapy. Vigorous multienzyme-like activities can not only produce O2 to alleviate hypoxia and promote the polarization of M2 to M1 macrophages but also generate ROS (•OH and 1 O2 ) and deplete GSH in the TME to expose necrotic cell fragments and reverse immunosuppressive TME by eliciting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes in tumors. Therefore, inhibitory effects on both primary and distant tumors were achieved through synergy with an α-PD-L1 blocking antibody. This cascade multienzyme-based nanoplatform provides a smart strategy for highly efficient ICB immunotherapy against "cold" tumors by revising immunosuppressive TME. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.