This Nature Biotechnology article introduces a novel trispecific macrophage engager (TrME) designed to overcome the limitations of current cancer immunotherapies in solid tumors. The researchers developed a molecular "AND" logic gate that simultaneously activates the prophagocytic LRP1 receptor and blocks the inhibitory SIRPα receptor on the same macrophage. By utilizing computationally guided design and a specialized chimeric linker library, the team identified an optimal configuration for stable cis-targeting, which ensures these dual signals are coordinated within a single immune cell. To enhance delivery and durability, the therapy is administered via an optimized lipid nanoparticle (LNP)-mRNA system, allowing for sustained in situ protein production. Experimental results in various mouse models, including glioblastoma and bladder cancer, demonstrate that the TrME effectively reprograms macrophages toward an anti-tumor state and stimulates a robust adaptive T cell response. Ultimately, this modular platform offers a highly precise method for enhancing macrophage-mediated killing while minimizing systemic toxicity across diverse cancer types.

References:

• Zhao X, Jing W, Wang G, et al. A logic-gated trispecific engager enhances macrophage killing of cancer cells in solid tumors[J]. Nature Biotechnology, 2026: 1-16.