Bispecific Immune Cell Engagers for Solid Tumors: Molecular Engineering and Therapeutic Perspectives

Bispecific immune cell engagers are among the most promising modalities in cancer immunotherapy, having made a significant impact on the treatment of hematological malignancy. However, their translation to solid tumors has remained challenging, leaving a critical gap for most cancer patients. A central obstacle is the lack of a mechanistic framework that integrates the complex biology of solid tumors with clinical outcomes, preventing a coherent interpretation of trial failures and impeding the development of more effective strategies. This review addresses that gap. We have reviewed clinical data from diverse engager formats recruiting T cells, NK cells, γδ T cells and monocytes across both successful and discontinued programs, showing how target selection, antigen accessibility, effector choice and molecular engineering collectively determine efficacy, half-life, tolerability and durability of response. We thereby construct a clinically grounded framework for designing next-generation engagers.