From T Cell Engagers to Next-Generation Immune Cell Engagers for Cancer Immunotherapy

Abstract Immune cell engagers have emerged as a powerful class of multi-specific therapeutics that redirect immune effector cells toward tumor cells to induce targeted cytotoxicity. Among these, T cell engagers (TCEs) represent the most clinically advanced platform, with multiple approved agents demonstrating substantial efficacy in hematologic malignancies. However, their broader application remains limited by systemic toxicities, antigen heterogeneity, and reduced efficacy in solid tumors. To address these challenges, next-generation TCEs are being engineered with improved selectivity, and optimized signaling properties. In parallel, increasing attention has shifted toward engaging alternative immune effectors, including γδ T cells, natural killer (NK) cells, and myeloid populations, which provide complementary mechanisms of tumor recognition and immune modulation. In this Review, we summarize the biological principles underlying T or other immune cell engagers, highlight emerging alternative platforms, and discuss evolving engineering strategies that are shaping the future of programmable cancer immunotherapy.