AbstractThe 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.

摘要肿瘤微环境可以通过诸如不良运输和免疫细胞耗竭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（大肠杆菌）的安全性，肿瘤嗜性和易遗传操作性，通过在大肠杆菌外膜上的表面展示向肿瘤递送关键的免疫激活细胞因子。

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.

大肠杆菌K-12 DH5α。表达鼠诱饵抗性IL18 mutein（DR18）的非致病性大肠杆菌在免疫活性结直肠癌和黑素瘤小鼠模型中诱导强烈的CD8+T和自然杀伤（NK）细胞依赖性免疫应答并抑制肿瘤进展。E、 大肠杆菌K-12 DH5α工程化以显示人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，其通过增强TNF信号传导和上调NK活化标志物来延长NK细胞治疗抗性间皮瘤异种移植模型中的存活。

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..

我们的基于活细菌的免疫治疗系统安全有效地诱导耐药实体瘤产生有效的抗肿瘤反应，促使临床进一步评估这种方法。。

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Fig. 1: Murine DR18 displayed by bacterial scaffold Lpp–OmpA induces potent anti-tumor responses in an immune-competent syngeneic mouse model (MC38).Fig. 2: Systemically delivered tumor-homing OmpA–mDR18 E. coli induces an abscopal effect and is safe.Fig. 3: Tumor control by OmpA–mDR18 is mediated by CD8+ T cells and NK cells in the TME.Fig.

图1：细菌支架Lpp-OmpA显示的鼠DR18在具有免疫能力的同基因小鼠模型（MC38）中诱导有效的抗肿瘤反应。图2：全身递送的肿瘤归巢OmpA-mDR18大肠杆菌诱导远隔效应并且是安全的。图3:OmpA-mDR18对肿瘤的控制是由TME中的CD8+T细胞和NK细胞介导的。。

4: Bacteria displaying hDR18 enhance anti-tumor responses of MSLN-CAR NK cells.Fig. 5: Bacteria displaying hDR18 enhance the proliferation, tumor trafficking and efficacy of MSLN-CAR NK cells in vivo, leading to improved tumor control.Fig. 6: Gene expression changes in the MSLN-CAR NK cells induced by priming with E.

4： 显示hDR18的细菌增强MSLN-CAR NK细胞的抗肿瘤反应。图5：显示hDR18的细菌增强体内MSLN-CAR NK细胞的增殖，肿瘤运输和功效，从而改善肿瘤控制。图6：用E引发诱导的MSLN-CAR NK细胞中的基因表达变化。

coli hDR18..

大肠杆菌hDR18。。

Data availability

数据可用性

All data generated during this study are available within the paper. The bulk RNA-seq data were deposited to the Gene Expression Omnibus under accession number GSE275391 (ref. 60). Datasets from the MSigDB were used in this study. Source data are provided with this paper.

本研究期间产生的所有数据均可在本文中找到。大量RNA-seq数据以登录号GSE275391（参考文献60）保藏到Gene Expression Omnibus。本研究使用了MSigDB的数据集。本文提供了源数据。

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Yang，S。等人。显示诱饵抗性IL18突变蛋白的非致病性大肠杆菌增强了癌症免疫疗法的功效（NCBI，2024）；https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE275391Download参考文献致谢这项工作得到了美国国立卫生研究院1DP2GM154019（J.L.），临床研究者奖（R.R.），NEU-DFCI合作基金（R.R.，J.L.）的支持。

and D.B.) and the Dana-Farber Sidney Farber Scholar Program (M.S.). R.R. received funding from the Parker Institute for Cancer Immunotherapy and is a recipient of a Career Development Award from the Leukemia & Lymphoma Society. We would like to express our gratitude to S. Rouhanifard at Northeastern University’s Department of Bioengineering for generously sharing her laboratory’s equipment and space with us; G.

和D.B.）和Dana-Farber-Sidney-Farber学者计划（M.S.）。R、 R.获得了帕克癌症免疫治疗研究所的资助，并且是白血病和淋巴瘤协会职业发展奖的获得者。；G。

Rong at the Institute for Chemical Imaging of Living Systems at Northeastern University for providing the confocal microscope equipment and relevant training; and Y. Li from SunVax mRNA Therapeutics for helpful and substantial suggestions. The cartoons were created using BioRender (https://biorender.com/).

东北大学生命系统化学成像研究所的荣提供了共聚焦显微镜设备和相关培训；和SunVax mRNA Therapeutics的Y.Li提供了有益和实质性的建议。这些卡通是用BioRender创作的(https://biorender.com/)。

Figures were generated by GraphPad Prism (version 10.1.1) and Adobe Illustrator (version 27.5).Author informationAuthor notesThese authors contributed equally: Shaobo Yang, Michal Sheffer.Authors and AffiliationsDepartment of Bioengineering, Northeastern University, Boston, MA, USAShaobo Yang, Ke Zhang, Valeria Márquez-Pellegrin, Shanna Bonanno, Ming Guan, Mengdi Yang, Deng Li & Chiara BelliniDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USAShaobo Yang, Michal Sheffer, Isabel E.

图形由GraphPad Prism（版本10.1.1）和Adobe Illustrator（版本27.5）生成。作者信息作者注意到这些作者做出了同样的贡献：杨少波，迈克尔·谢弗。作者和附属机构东北大学生物工程系，波士顿，马萨诸塞州，美国杨少波，张科，瓦莱丽亚·马尔克斯·佩莱格林，香娜·博南诺，明关，孟迪·杨，邓丽和奇亚拉·贝利尼医学肿瘤学系，达纳·法伯癌症研究所，波士顿，马萨诸塞州，美国杨少波，Michal Sheffer，Isabel E。

Kaplan, Mubin Tarannum, Khanhlinh Dinh, Yasmin Abdulhamid, Eden Bobilev, Roman Shapiro, Rebecca Porter, Robert Soiffer, Jerome Ritz, John Koreth, Fuguo Li.

卡普兰（Kaplan）、穆宾·塔兰努姆（Mubin Tarannum）、坎林·丁（Khanhlinh Dinh）、亚斯敏·阿卜杜勒哈米德（Yasmin Abdulhamid）、伊登·波比列夫（Eden Bobilev）、罗马·夏皮罗（Roman Shapiro）、丽贝卡·波特（Rebecca Porter）、罗伯特·索弗（Robert Soiffer）、杰。

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PubMed Google ScholarContributionsJ.L., R.R, S.Y. and M.S. conceptualized the study. S.Y., M.S., R.R. and J.L. wrote the paper. S.Y., M.S. and Z.W. designed the experiments and performed analysis and data interpretation. S.Y., M.S., I.E.K., Z.W., M.T., K.D., Y.A., E.B., Y.W., P.C., V.M.-P., S.B., F.L., M.G.

PubMed谷歌学术贡献。五十、 ，R.R，S.Y.和M.S.对这项研究进行了概念化。S、 Y.，M.S.，R.R.和J.L.写了这篇论文。S、 Y.，M.S.和Z.W.设计了实验并进行了分析和数据解释。S、 Y.，M.S.，I.E.K.，Z.W.，M.T.，K.D.，Y.A.，E.B.，Y.W.，P.C.，V.M.-P.，S.B.，F.L.，M.G。

and M.Y. performed the experiments. S.Y. and D.L. predicted and analyzed the protein structure. M.S., I.E.K., E.B. and Y.A. prepared NK cells. J.L., R.R., N.J., K.Z. and C.B. guided during the optimization and assisted during the experimental procedures and analysis. R. Shapiro., R.P., R. Soiffer, J.R., J.K., J.C., C.J.W.

和M.Y.进行了实验。S、 Y.和D.L.预测并分析了蛋白质结构。M、 美国，即英国，E.B.和Y.A.制备的NK细胞。J、 L.，R.R.，N.J.，K.Z.和C.B.在优化过程中进行了指导，并在实验程序和分析过程中提供了帮助。R、 夏皮罗。，R、 P.，R.Soiffer，J.R.，J.K.，J.C.，C.J.W。

and D.B. substantively revised the final version of the paper.Corresponding authorsCorrespondence to.

D.B.对论文的最终版本进行了实质性修改。通讯作者通讯。

Jiahe Li or Rizwan Romee.Ethics declarations

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Competing interests

相互竞争的利益

R.R., J.L., S.Y. and M.S. are named inventors on a patent application that describes the surface display of engineered bacteria. R.R. has sponsored research agreements with CRISPR Therapeutics and Skyline Therapeutics and serves on the scientific advisory board of Glycostem Therapeutics. R.R. and J.C.

R、 R.，J.L.，S.Y.和M.S.是一项描述工程细菌表面展示的专利申请的发明人。R.R.赞助了与CRISPR Therapeutics和Skyline Therapeutics的研究协议，并担任Glycostem Therapeutics科学咨询委员会的成员。R、 R.和J.C。

are co-founders of InnDura Therapeutics. J.R. received research funding from Kite/Gilead, Novartis and Oncternal Therapeutics and serves on advisory boards for Akron Biotech, Clade Therapeutics, Garuda Therapeutics, LifeVault Bio, Novartis and Smart Immune. The other authors declare no competing interests..

是InnDura Therapeutics的联合创始人。J、 R.获得了Kite/Gilead，Novartis和Oncentral Therapeutics的研究资金，并担任Akron Biotech，Clade Therapeutics，Garuda Therapeutics，LifeVault Bio，Novartis和Smart Immune的咨询委员会成员。其他作者声明没有利益冲突。。

Peer review

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Peer review information

同行评审信息

Nature Biotechnology thanks Laurence Zitvogel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

《自然生物技术》感谢劳伦斯·齐特沃格尔（LaurenceZitvogel）和另一位匿名审稿人对这项工作的同行评审做出的贡献。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 Treatment with the engineered bacteria induces immunological memory leading to enhanced recall responses (MC38).a, b, C57BL/6 mice (n = 5) cured from MC38 upon treatment with OmpA-mDR18 and naïve C57BL/6 (gender and age-matched with the cured mice) were subcutaneously (s.c.) engrafted with 0.5 x 106 MC38 cells and then monitored for tumor growth and survival.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据扩展数据图1用工程菌处理诱导免疫记忆，导致增强的回忆反应（MC38）。a，b，用OmpA-mDR18和幼稚C57BL/6（性别和年龄与治愈的小鼠匹配）治疗后从MC38治愈的C57BL/6小鼠（n=5）皮下（s.c.）移植0.5×106 MC38细胞，然后监测肿瘤生长和存活。

Mean tumor growth (a) and Kaplan– Meier survival curves (b) for mice injected with 0.5 x 106 MC38 cells on Day 0. Two-way ANOVA test for tumor growth curve (a) and Mantel-Cox test for survival curve (b). Data are representative of one independent experiment, with n = 5 mice per group (a, b). Data represent means ± SD (a).Source dataExtended Data Fig.

在第0天注射0.5 x 106 MC38细胞的小鼠的平均肿瘤生长（a）和Kaplan-Meier生存曲线（b）。。数据代表一个独立实验，每组n=5只小鼠（a，b）。数据代表平均值±SD（a）。源数据扩展数据图。

2 Treatment with the engineered bacteria induces immunological memory leading to enhanced recall responses (B16F10).a, b, C57BL/6 mice (n = 3) cured from B16F10 upon treatment with OmpA-mDR18 and naïve C57BL/6 (gender and age-matched with the cured mice) were subcutaneously (s.c.) engrafted with 0.5 x 106 B16F10 cells and then monitored for tumor growth and survival.

2用工程菌处理诱导免疫记忆，导致回忆反应增强（B16F10）。a，b，用OmpA-mDR18和幼稚C57BL/6（性别和年龄）治疗后从B16F10治愈的C57BL/6小鼠（n=3）与治愈的小鼠相匹配）皮下（s.c.）移植0.5×106 B16F10细胞，然后监测肿瘤生长和存活。

Mean tumor growth (a) and Kaplan–Meier survival curves (b) for mice injected with 0.5 x 106 B16F10 cells on Day 0. Two-way ANOVA test for tumor growth curve (a) and Mantel-Cox test for survival curve (b). Data are representative of one independent experiment, with n = 3 mice per group (a, b). Data represent means ± SD (a).Source dataExtended Data Fig.

在第0天注射0.5×106 B16F10细胞的小鼠的平均肿瘤生长（a）和Kaplan-Meier存活曲线（b）。。数据代表一个独立实验，每组n=3只小鼠（a，b）。数据代表平均值±SD（a）。源数据扩展数据图。

3 Co-administration of OmpA-mDR18 and anti-PD-1 increases anti-tumor responses in an immune-competent syngeneic mouse model (MC38).a, C57BL/6 mice were subcutaneously (s..

3 OmpA-mDR18和抗PD-1的共同给药增加了免疫活性同系小鼠模型（MC38）中的抗肿瘤反应。a，C57BL/6小鼠皮下（s。。

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