School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, China.
Department of Pharmacy, The First Hospital of Yulin (The Second Affiliated Hospital of Yan'an University), China.
Acta Biomater. 2024 Jan 1;173:378-388. doi: 10.1016/j.actbio.2023.10.037. Epub 2023 Nov 3.
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 MnO (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 Mn, GOX and CB839. On the one hand, Mn can convert HO 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.
免疫疗法是一种新兴的肿瘤治疗方法，可用于手术、放疗和化疗后的肿瘤治疗。尽管免疫疗法具有消除原发性肿瘤细胞和抑制癌症转移的潜力，但仍面临巨大挑战，包括肿瘤免疫原性低和不理想的免疫抑制肿瘤微环境（TME）。在此，开发了一种双管齐下的微环境调节纳米平台来克服这些局限性。具体来说，制备了具有 pH 响应性的中空介孔 MnO（HM）纳米粒子，并通过酰胺键将其与葡萄糖氧化酶（GOX）进行修饰，然后进一步负载有效的谷氨酰胺酶抑制剂 CB839，得到 HM-GOX/CB839。在 TME 中的低 pH 值下，HM 会分解，从而释放出 Mn、GOX 和 CB839。一方面，Mn 可以通过肿瘤中 GOX 催化生成的 HO 转化为高毒性的羟基自由基（•OH），并通过金属氧化酶级联催化反应进一步诱导免疫原性细胞死亡（ICD），增强免疫原性。另一方面，GOX 和 CB839 可以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的数量并重塑 TME，提高抗肿瘤免疫疗效。结果表明，HM-GOX/CB839 可有效激活机体免疫，抑制肿瘤生长和转移，为肿瘤的综合治疗提供了一种潜在策略。
意义陈述：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一种潜在的途径。在此前提下，我们构建了一种双管齐下的微环境调节纳米平台（HM-GOX/CB839）。一方面，金属氧化酶级联反应可以催化生成羟基自由基（•OH）并诱导免疫原性细胞死亡（ICD），增强免疫原性；另一方面，代谢干预可重新编程肿瘤微环境以减轻免疫抑制，从而增强抗肿瘤免疫反应。结果表明，HM-GOX/CB839 能有效抑制肿瘤生长和转移，为癌症免疫治疗提供了治疗潜力。
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