免疫治疗是继手术、放疗、化疗之后新兴的肿瘤治疗方式。尽管免疫疗法具有消除原发肿瘤细胞和抑制癌症转移的潜力，但仍面临巨大的挑战，包括低肿瘤免疫原性和不良的免疫抑制肿瘤微环境（TME）。在此，开发了双管齐下的微环境调节纳米平台来克服这些限制。具体而言，制备具有pH响应特性的中空介孔MnO2（HM）纳米粒子，并用葡萄糖氧化酶（GOX）通过酰胺键对其进行修饰，并进一步负载有效的谷氨酰胺酶抑制剂CB839，得到HM-GOX/CB839。在 TME 的低 pH 值下，HM 崩解，从而释放出 Mn2 、GOX 和 CB839。一方面，Mn可以将肿瘤内GOX催化增加的H2O2转化为剧毒的羟基自由基（·OH），并进一步通过金属氧化酶级联催化反应诱导免疫原性细胞死亡（ICD），增强免疫原性。另一方面，GOX和CB839可分别阻断糖酵解和谷氨酰胺代谢途径，有效减少免疫抑制细胞数量，重塑TME，提高抗肿瘤免疫功效。研究表明，HM-GOX/CB839能够有效激活机体免疫力，抑制肿瘤生长和转移，为肿瘤综合治疗提供潜在策略。意义声明：：金属氧化酶级联催化和代谢干预的综合微环境调节为肿瘤免疫治疗提供了潜在的途径。在此前提下，我们构建了双管齐下的微环境调节纳米平台（HM-GOX/CB839）。一方面，金属氧化酶级联可以催化羟自由基（•OH）的产生并诱导免疫原性细胞死亡（ICD），增强免疫原性；另一方面，代谢干预通过重新编程肿瘤微环境来缓解免疫抑制，从而增强抗肿瘤免疫反应。结果数据表明，HM-GOX/CB839 有效抑制肿瘤生长和转移，为癌症免疫疗法提供了治疗潜力。版权所有 © 2023。由 Elsevier Ltd 出版。

Immunotherapy is an emerging treatment modality for tumors after surgery, radiotherapy, and chemotherapy. Despite the potential for eliminating primary tumor cells and depressing cancer metastasis, immunotherapy has huge challenges including low tumor immunogenicity and undesirable immunosuppressive tumor microenvironment (TME). Herein, the two-pronged microenvironmental modulation nanoplatform is developed to overcome these limitations. Specifically, hollow mesoporous MnO2 (HM) nanoparticles with pH responsive property are prepared and modified with glucose oxidase (GOX) by amide bond, which are further loaded with a potent glutaminase inhibitor CB839 to obtain HM-GOX/CB839. Under the low pH values in TME, HM was disintegrated, thereby releasing Mn2+, GOX and CB839. On the one hand, Mn2+ can convert H2O2 that increased by GOX catalysis in tumors into highly toxic hydroxyl radicals (•OH) and further induce immunogenic cell death (ICD) through the metal-oxidase cascade catalytic reaction, enhancing immunogenicity. On the other hand, GOX and CB839 can block glycolytic and glutamine metabolism pathways, respectively, which effectively reduce the number of immunosuppressive cells and reshape TME, improving anti-tumor immune efficacy. It is demonstrated that HM-GOX/CB839 can effectively activate the body's immunity and inhibit tumor growth and metastasis, providing a potential strategy for comprehensive tumor therapy. STATEMENT OF SIGNIFICANCE: : Integrated microenvironmental modulation of metal-oxidase cascade catalysis and metabolic intervention offers a potential avenue for tumor immunotherapy. Under this premise, we constructed a two-pronged microenvironmental modulation nanoplatform (HM-GOX/CB839). On the one hand, the metal oxidase cascade could catalyze the generation of hydroxyl radicals (•OH) and induce immunogenic cell death (ICD), enhancing immunogenicity; on the other hand, metabolic intervention reprogrammed tumor microenvironment to relieve immunosuppression and thereby enhancing anti-tumor immune response. The resulting data demonstrated that HM-GOX/CB839 effectively inhibited tumor growth and metastasis, providing therapeutic potential for cancer immunotherapy.Copyright © 2023. Published by Elsevier Ltd.