Stinson Jordan A, Sheen Allison, Lax Brianna M, Yang Grace N, Duhamel Lauren, Santollani Luciano, Fink Elizabeth, Palmeri Joseph R, Wittrup Karl Dane
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Mol Cancer Ther. 2025 Jan 2;24(1):118-130. doi: 10.1158/1535-7163.MCT-24-0163.
Although heightened intratumoral levels of reactive oxygen species (ROS) are typically associated with a suppressive tumor microenvironment, under certain conditions ROS contribute to tumor elimination. Treatment approaches, including some chemotherapy and radiation protocols, increase cancer cell ROS levels that influence their mechanism of cell death and subsequent recognition by the immune system. Furthermore, activated myeloid cells rapidly generate ROS upon encounter with pathogens or infected cells to eliminate disease, and recently, this effector function has been noted in cancer contexts as well. Collectively, ROS-induced cancer cell death may help initiate adaptive antitumor immune responses that could synergize with current approved immunotherapies, for improved control of solid tumors. In this work, we explore the use of glucose oxidase, an enzyme which produces hydrogen peroxide, a type of ROS, to therapeutically mimic the endogenous oxidative burst from myeloid cells to promote antigen generation within the tumor microenvironment. We engineer the enzyme to target pan-tumor-expressed integrins both as a tumor-agnostic therapeutic approach and as a strategy to prolong local enzyme activity following intratumoral administration. We found the targeted enzyme potently induced cancer cell death and enhanced cross-presentation by dendritic cells in vitro and further combined with interferon alpha for long-term tumor control in murine MC38 tumors in vivo. Optimizing the single-dose administration of this enzyme overcomes limitations with immunogenicity noted for other prooxidant enzyme approaches. Overall, our results suggest ROS-induced cell death can be harnessed for tumor control and highlight the potential use of designed enzyme therapies alongside immunotherapy against cancer.
尽管肿瘤内活性氧（ROS）水平升高通常与抑制性肿瘤微环境相关，但在某些情况下，ROS有助于消除肿瘤。包括一些化疗和放疗方案在内的治疗方法会增加癌细胞的ROS水平，这会影响其细胞死亡机制以及随后被免疫系统识别的过程。此外，活化的髓系细胞在遇到病原体或感染细胞时会迅速产生活性氧以消除疾病，最近，这种效应功能在癌症背景下也被注意到。总的来说，ROS诱导的癌细胞死亡可能有助于启动适应性抗肿瘤免疫反应，这可能与目前批准的免疫疗法协同作用，以更好地控制实体瘤。在这项工作中，我们探索使用葡萄糖氧化酶，一种产生过氧化氢（一种ROS）的酶，来治疗性模拟髓系细胞的内源性氧化爆发，以促进肿瘤微环境内的抗原产生。我们对该酶进行工程改造，使其靶向全肿瘤表达的整合素，这既是一种与肿瘤无关的治疗方法，也是一种在瘤内给药后延长局部酶活性的策略。我们发现，靶向酶在体外能有效诱导癌细胞死亡并增强树突状细胞的交叉呈递，并且在体内与α干扰素联合使用，可长期控制小鼠MC38肿瘤。优化这种酶的单剂量给药克服了其他促氧化酶方法所存在的免疫原性限制。总体而言，我们的结果表明，ROS诱导的细胞死亡可用于肿瘤控制，并突出了设计酶疗法与癌症免疫疗法联合使用的潜力。
