AbstractTargeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance therapeutics for blocking macrophage phagocytosis checkpoint inhibitors in solid tumors. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions.

摘要用于重新激活先天细胞，特别是巨噬细胞的靶向免疫调节有望补充当前的适应性免疫疗法。然而，仍然缺乏用于阻断实体瘤中巨噬细胞吞噬作用检查点抑制剂的高效治疗剂。在此，描述了肽-抗体组合超分子原位组装的CD47和CD24双靶抑制剂（PAC-SABI），其通过配体-受体结合和酶触发反应在癌细胞膜上进行仿生表面传播。

By simultaneously blocking CD47 and CD24 signaling, PAC-SABI enhances the phagocytic ability of macrophages in vitro and in vivo, promoting anti-tumor responses in breast and pancreatic cancer mouse models. Moreover, building on the foundation of PAC-SABI-induced macrophage repolarization and increased CD8+ T cell tumor infiltration, sequential anti-PD-1 therapy further suppresses 4T1 tumor progression, prolonging survival rate.

通过同时阻断CD47和CD24信号传导，PAC-SABI在体外和体内增强巨噬细胞的吞噬能力，促进乳腺癌和胰腺癌小鼠模型中的抗肿瘤反应。此外，在PAC-SABI诱导的巨噬细胞复极化和CD8+T细胞肿瘤浸润增加的基础上，序贯抗PD-1治疗进一步抑制4T1肿瘤进展，延长生存率。

The in vivo construction of PAC-SABI-based nano-architectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency..

基于PAC-SABI的纳米结构的体内构建为桥接先天性和适应性免疫以最大程度地提高治疗效力提供了有效的平台。。

IntroductionAdaptive immune checkpoint (IC) inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand programmed death-ligand 1 (PD-L1) have shown efficacy in treating some cancer types by disrupting inhibitory T cell pathways1,2,3. Unfortunately, their effectiveness remains limited against immune quiescent tumors, such as breast and pancreatic cancers (BCs and PCs), underscoring the importance of innate immune cells and enhanced antigen processing to overcome this challenge4,5,6.

简介靶向程序性细胞死亡蛋白1（PD-1）或其配体程序性死亡配体1（PD-L1）的适应性免疫检查点（IC）抑制剂已显示出通过破坏抑制性T细胞途径治疗某些癌症类型的功效1,2,3。不幸的是，它们对免疫静止性肿瘤（如乳腺癌和胰腺癌（BC和PC））的有效性仍然有限，强调了先天免疫细胞和增强抗原加工对克服这一挑战的重要性4,5,6。

As the highly prevalent non-malignant cells in tumor microenvironment (TME), macrophages play a crucial innate immune role via phagocytosis, antigen presentation, and inflammatory cytokine production, linking innate and adaptive immunity5,7. Yet cancer cells can evade macrophage clearance by upregulating anti-phagocytic “don’t eat me” membrane proteins8,9,10,11.

作为肿瘤微环境（TME）中高度流行的非恶性细胞，巨噬细胞通过吞噬作用，抗原呈递和炎性细胞因子产生发挥关键的先天免疫作用，将先天免疫和适应性免疫联系起来5,7。。

Thus, inhibiting these antiphagocytic signals or receptors represents a promising immunotherapeutic approach that could synergize with cancer cell elimination, activate CD8+ T cells, and initiate an antitumor immune response.The CD47-signal regulatory protein alpha (SIRPα) axis, discovered in the late 2000s, was the first identified checkpoint inhibiting cancer phagocytosis through innate immunity12,13,14.

因此，抑制这些抗吞噬信号或受体代表了一种有前途的免疫治疗方法，可以与癌细胞消除协同作用，激活CD8+T细胞，并启动抗肿瘤免疫应答。2000年代末发现的CD47信号调节蛋白α（SIRPα）轴是第一个通过先天免疫抑制癌症吞噬作用的检查点12,13,14。

Clinical trials are ongoing to test inhibitors and antibodies targeting this axis for cancer therapy. However, two primary challenges have hindered their successful clinical application15. One is the ubiquitous CD47 expression on normal cells (“antigen sink”), especially red blood cells and platelets.

临床试验正在进行中，以测试针对该轴的抑制剂和抗体用于癌症治疗。然而，两个主要挑战阻碍了它们成功的临床应用15。一种是正常细胞（“抗原库”）上普遍存在的CD47表达，尤其是红细胞和血小板。

High maintenance dosing required to saturate peripheral antigens causes severe toxicity like anemia and thrombocytopenia16. The other challenge is the limited treatment response in solid tumors17,18, likely due to additi.

使外周抗原饱和所需的高维持剂量会导致严重的毒性，如贫血和血小板减少16。另一个挑战是实体瘤的治疗反应有限17,18，可能是由于ADTITI。

Data availability

数据可用性

RNA-seq data that support the findings of this study have been deposited in the NCBI Sequence Read Archive under the BioProject ID PRJNA1124390. RNA-seq data based on the TCGA and Genotype-Tissue Expression (GTEx) projects, obtained from the Gene Expression Profiling Interactive Analysis 2 (GEPIA2, http://gepia2.cancer-pku.cn) database, were used to investigate the expression of CD47 and CD24 in tumor and paired normal tissue, and to conduct survival analysis.

支持本研究结果的RNA-seq数据已保存在生物项目ID PRJNA1124390下的NCBI序列读取档案中。基于TCGA和基因型组织表达（GTEx）项目的RNA-seq数据，从基因表达谱交互分析2（GEPIA2，http://gepia2.cancer-pku.cn)数据库，用于研究CD47和CD24在肿瘤和配对正常组织中的表达，并进行生存分析。

The remaining data generated in this study are available within the Article, Supplementary Information or Source Data file. Source data are provided with this paper..

本研究中生成的其余数据可在文章，补充信息或源数据文件中找到。本文提供了源数据。。

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Download referencesAcknowledgementsWe acknowledge the financial support from National Natural Science Foundation of China (51973090 to Y.C., 32271372 to Y.C., 31900952 to Y.C., 32101058 to J.Z., 82273256 to N.L.), Guangdong Basic and Applied Basic Research Foundation (2023A1515012734 to J.Z., 2023A1515110674 to W.Z.), Science and Technology Projects of Guangzhou (2024A04J5154 to J.Z., 2024A04J4490 to W.Z.).

下载参考文献致谢我们感谢国家自然科学基金（51973090至Y.C.，32271372至Y.C.，31900952至Y.C.，32101058至J.Z.，82273256至N.L.），广东基础与应用基础研究基金（2023A15127234至J.Z.，2023A15110674至W.Z.），广州科技项目（2024A04J5154至J.Z.，2024A04J4490至W.Z.）。

China Postdoctoral Science Foundation (2023M740768 to W.Z.). Postdoctoral Fellowship Program of CPSF to W.Z.Author informationAuthor notesThese authors jointly supervised this work: Jie Zhan, Ning Liao, Yanbin Cai.Authors and AffiliationsGuangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, ChinaWeiqi Zhang & Yinghua ZengDepartment of Breast Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, ChinaWeiqi Zhang, Yuting Luo & Ning LiaoGuangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, ChinaWeiqi Zhang, Yinghua Zeng, Qiuqun Xiao, Jiale Liu & Yanbin CaiDepartment of Cardiology and Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, ChinaYinghua Zeng, Qiuqun Xiao, Jiale Liu & Yanbin CaiDepartment of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, ChinaYuanyuan WuDepartment of Gastrointestinal Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, ChinaHaocheng WangDepartment of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaJie ZhanGuangdong Engineering and Tech.

中国博士后科学基金会（2023M740768至W.Z.）。CPSF对W.Z.作者信息的博士后奖学金项目作者注意到这些作者共同监督了这项工作：Jie Zhan，Ning Liao，Yanbin Cai。作者和单位广东省人民医院广东省心血管研究所，广东省医学科学院，南方医科大学，广州，中国张伟奇，曾英华广东省人民医院乳腺外科，广东省医学科学院，南方医科大学，广州，中国张伟奇，罗玉婷，廖宁宁广东省心血管疾病生物医学工程技术研究中心，南方医科大学珠江医院，广州，中国张伟奇，曾英华，肖秋群，刘家乐，蔡燕斌南方医科大学珠江医院心脏病学与心脏中心实验室，广州，曾英华，肖秋群，刘家乐和蔡燕斌南方医科大学珠江医院肝胆外科，广州，中国南方医科大学珠江医院胃肠外科，广州，中国王浩成南方医科大学南方医院检验科，中国广州张广东工程技术有限公司。

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PubMed Google ScholarContributionsW.Z., N.L. and Y.C. conceived the study and designed the experiments. W.Z., Q.X. and J.Z. carried out the synthesis and characterization of the PAC-SABIs. W.Z. and Y.L. collected clinical data and samples. W.Z., H.W. and N.L. performed single-cell RNA sequencing and analysis.

PubMed谷歌学术贡献软件。Z、 ，N.L.和Y.C.构思了这项研究并设计了实验。W、 。W、 Z.，H.W.和N.L.进行了单细胞RNA测序和分析。

W.Z., Y.Z., Y.W., J.L. and Y.L. performed all the in vitro and in vivo experiments. W.Z., Y.Z. and Y.C. discussed the results, interpreted the data, wrote and revised the paper. J.Z., N.L. and Y.C. supervised the research. All authors read and approved the final version of the manuscript.Corresponding authorsCorrespondence to.

W、 Z.，Y.Z.，Y.W.，J.L.和Y.L.进行了所有的体外和体内实验。W、 Z.，Y.Z.和Y.C.讨论了结果，解释了数据，撰写并修订了论文。J、 。所有作者都阅读并批准了稿件的最终版本。通讯作者通讯。

Jie Zhan, Ning Liao or Yanbin Cai.Ethics declarations

詹杰、廖宁或蔡燕斌。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

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Nature Communications thanks Charlotte Hauser and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

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Reprints and permissionsAbout this articleCite this articleZhang, W., Zeng, Y., Xiao, Q. et al. An in-situ peptide-antibody self-assembly to block CD47 and CD24 signaling enhances macrophage-mediated phagocytosis and anti-tumor immune responses.

转载和许可本文引用本文Zhang，W.，Zeng，Y.，Xiao，Q。等人。阻断CD47和CD24信号传导的原位肽抗体自组装增强巨噬细胞介导的吞噬作用和抗肿瘤免疫应答。

Nat Commun 15, 5670 (2024). https://doi.org/10.1038/s41467-024-49825-6Download citationReceived: 31 August 2023Accepted: 20 June 2024Published: 06 July 2024DOI: https://doi.org/10.1038/s41467-024-49825-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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