肿瘤微环境可以通过运输不良和免疫细胞耗尽等机制抑制癌症治疗的功效。在这里，为了应对这一挑战，我们利用非致病性大肠杆菌 (E. coli) 的安全性、肿瘤向性和易于遗传操作的特性，通过大肠杆菌外膜上的表面展示将关键的免疫激活细胞因子传递到肿瘤K-12 DH5α。在具有免疫活性的结直肠癌和黑色素瘤小鼠模型中，表达鼠诱饵抗性 IL18 突变蛋白 (DR18) 的非致病性大肠杆菌可诱导强大的 CD8 T 和自然杀伤 (NK) 细胞依赖性免疫反应，并抑制肿瘤进展。大肠杆菌 K-12 DH5α 经工程改造，可展示人 DR18 有效激活的间皮素靶向嵌合抗原受体 (CAR) NK 细胞，并增强其向肿瘤的运输，从而通过增强 TNF 信号传导和上调 NK 激活标记。我们基于活细菌的免疫治疗系统可以安全有效地在难治性实体瘤中诱导有效的抗肿瘤反应，从而促进在临床上进一步评估这种方法。© 2024。作者获得 Springer Nature America 的独家许可，公司

The tumor microenvironment can inhibit the efficacy of cancer therapies through mechanisms such as poor trafficking and exhaustion of immune cells. Here, to address this challenge, we exploited the safety, tumor tropism and ease of genetic manipulation of non-pathogenic Escherichia coli (E. coli) to deliver key immune-activating cytokines to tumors via surface display on the outer membrane of E. coli K-12 DH5α. Non-pathogenic E. coli expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8+ T and natural killer (NK) cell-dependent immune responses and suppressed tumor progression in immune-competent colorectal carcinoma and melanoma mouse models. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting chimeric antigen receptor (CAR) NK cells and enhance their trafficking into tumors, which extended survival in an NK cell treatment-resistant mesothelioma xenograft model by enhancing TNF signaling and upregulating NK activation markers. Our live bacteria-based immunotherapeutic system safely and effectively induces potent anti-tumor responses in treatment-resistant solid tumors, motivating further evaluation of this approach in the clinic.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.