Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment.

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Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME. We developed the triple orthogonal linker (T-Linker) technology to integrate various therapeutic small molecules and biomolecules as multimodal targeting chimeras (Multi-TACs). The EGFR-CD3-PDL1 Multi-TAC facilitated T-dendritic cell co-engagement to target solid tumors with excellent efficacy, as demonstrated invitro, in several humanized mouse models and in patient-derived tumor models. Furthermore, Multi-TACs were constructed to coordinate Tcells with other immune cell types. The highly modular and programmable feature of our Multi-TACs may find broad applications in immunotherapy and beyond.