Designing T-cell Engagers: Trade-offs Between Activity and Safety.

T-cell engagers (TCEs) are an emerging class of immunotherapeutics that have demonstrated considerable clinical efficacy across a range of tumor types. However, their clinical application remains constrained by the challenge of balancing antitumor activity with acceptable safety, which is particularly prominent in solid malignancies. Multiple strategies have been explored to address this trade-off, including molecular engineering, dosing regimens, and patient selection. Nonetheless, within molecular design efforts, activity and toxicity are still largely optimized in isolation. Here, we provide a systematic analysis of the principal TCE design strategies, examining their respective strengths, limitations, and interdependencies. These strategies fall into two broad categories: those centered on the T-cell interface and those directed at the tumor cell. On the T-cell side, we review approaches that enable spatiotemporal control of T-cell activation through anti-CD3 affinity tuning, incorporation of costimulatory signals, and blockade of immunosuppressive pathways. On the tumor side, we discuss the use of antigen selection, binding valency and tumor microenvironment (TME)-responsive activation as means to enhance tumor-selective cytotoxicity. Although contemporary TCE formats afford increasingly sophisticated, format-driven modulation of function, deeper mechanistic insight into T-cell activation and TME biology will be essential to develop safer and more effective therapeutics. By integrating and critically comparing existing strategies, this review offers a holistic framework for navigating the activity-safety trade-off and provides guidance for next-generation TCE development.