Recently, the research team led by Prof. Jiang Xinyi at the School of Pharmaceutical Sciences at Shandong University published an article online in Nature Biotechnology entitled “A logic-gated trispecific engager enhances macrophage killing of cancer cells in solid tumors.” This study developed a logic-gated trispecific macrophage engager capable of integrating pro- and anti-phagocytic signals in a proportional manner, thereby significantly enhancing the tumoricidal activity of macrophages. Prof. Jiang Xinyi at Shandong University, Prof. Xing Nianzeng at Peking Union Medical College, and Prof. Zhang Junfeng at Nanjing University, among others, served as co-corresponding authors of this study. Zhao Xiaotian, a Ph.D. candidate at the School of Pharmaceutical Sciences of Shandong University, and Jing Weiqiang at Qilu Hospital of Shandong University, among others, are co-first authors of this paper.

Immune cell engagers (ICEs) are emerging targeted immunotherapies that bridge immune cells with tumor cells and direct immune cells to specifically eliminate tumors. Although ICEs have demonstrated remarkable efficacy in hematological malignancies, their application in solid tumors remains limited by the immunosuppressive tumor microenvironment, particularly due to insufficient immune cell activation. Macrophages, as key immune cells highly enriched in solid tumors, rely on a dynamic balance between pro-phagocytic and anti-phagocytic signals to regulate their phagocytic function. Existing therapeutic strategies predominantly focus on either enhancing or blocking a single signal, making it difficult to achieve coordinated integration of multiple signals within macrophages, which leads to insufficient activation and limited therapeutic efficacy.

The research team developed a logic-gated trispecific macrophage engager (TrME). This molecule is based on a computationally assisted cis-targeting strategy that simultaneously enhances activation signals of pro-phagocytic receptors while inhibiting anti-phagocytic receptor signaling on the macrophage surface, thereby establishing an “activation-blockade” AND logic gate to achieve precise proportional regulation of pro- and anti-phagocytic signals. At low doses, TrME markedly enhanced macrophage phagocytic efficiency and promoted macrophage polarization toward a pro-inflammatory phenotype, exhibiting overall superior efficacy compared with earlier bispecific antibodies.

They further developed a lipid nanoparticle (LNP) system, BCT-A5, which markedly improved the in vivo delivery efficiency of TrME mRNA and prolonged the duration of protein expression. A single administration was sufficient to maintain a sustained and therapeutically effective concentration at the tumor site. In multiple orthotopic models, including glioblastoma, bladder cancer, and breast cancer, TrME significantly inhibited tumor progression and prolonged survival. Mechanistic investigations revealed that TrME enhanced macrophage phagocytosis and antigen presentation and further promoted the recruitment and activation of CD8⁺ T cells. In bilateral tumor models, TrME inhibited distant tumor growth and induced epitope spreading, reflecting a systemic antitumor effect driven by the synergistic amplification of innate and adaptive immunity.

This study proposes a strategy for constructing immune cell engagers based on a cis-targeting logic-gated principle, providing a promising therapeutic approach to overcome immunosuppression in solid tumors. This work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, and other funding sources.