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  3. A logic-gated trispecific engager enhances macrophage killing of cancer cells in solid tumors

A logic-gated trispecific engager enhances macrophage killing of cancer cells in solid tumors

  • Nat Biotechnol. 2026 Mar 13. doi: 10.1038/s41587-026-03057-9.
Xiaotian Zhao # 1,  Weiqiang Jing # 2,  Ganyu Wang # 1,  Zhanyan Liu 1,  Xinxin Xu 1,  Maosen Han 1,  Zhipeng Fu 1,  Yulin Zhang 3,  Zuolin Zheng 1,  Jing Zhang 1,  Longyu Bo 1,  Xianghui Dong 1,  Caiping Li 1,  Yanhua Sun 4,  Junfeng Zhang 5,  Fabao Zhao 6,  Nianzeng Xing 7,  Kun Zhao 8,  Xinyi Jiang 9
Affiliations

Affiliations

  • 1 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences; Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 2 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences; Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. wjing1@sdu.edu.cn.
  • 3 Department of Neurosurgery, Qilu Hospital and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 4 Shandong Provincial Key Laboratory of Microparticles Drug Delivery Technology, Qilu Pharmaceutical Co., Ltd., Jinan, China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. jfzhang@nju.edu.cn.
  • 6 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences; Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. zhaofabao@email.sdu.edu.cn.
  • 7 Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. xingnianzeng@126.com.
  • 8 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences; Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. kzhao2013@sdu.edu.cn.
  • 9 Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences; Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. xinyijiang@sdu.edu.cn.
  • # Contributed equally.
PMID: 41826511 DOI: 10.1038/s41587-026-03057-9
Abstract

The antitumor efficacy of immune cell engagers that bind two targets on the same immune cell is limited by structural constraints, leading to incomplete coengagement and uncoordinated signaling. Here, we develop a trispecific macrophage engager (TrME) that both activates the prophagocytic receptor lipoprotein receptor-related protein 1 (LRP1) and blocks the antiphagocytic receptor signal regulatory protein alpha (SIRPα). This 'activate and block' AND logic gate, when coupled to a tumor-targeting moiety, enables coordinated signaling that enhances macrophage cytotoxicity against solid tumors. The TrME tandemly links monovalent LRP1 activator calreticulin, anti-SIRPα scFv and a tumor-associated antigen (TAA)-targeting arm through flexible linkers. Computational modeling and screening of tandem constructs revealed an optimal conformation for robust cis-targeting, allowing logic-gated control of ratiometric prophagocytic and antiphagocytic signaling. In situ generation of TrME by delivering mRNA encoding TAA-targeting TrME through an optimized lipid nanoparticle system activates macrophages and induces antitumor responses, significantly inhibiting tumor growth and prolonging survival in multiple solid tumor mouse models.

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