Related Experiment Video
Updated: Jun 6, 2026
Non-Viral Engineering of Primary Human T Cells via Homology-Mediated End-Joining Targeted Integration of Large DNA Templates
Published on: May 9, 2025
Designing T-cell Engagers: Trade-offs Between Activity and Safety
Yue Zhang1,2, Mengmeng Wei2,3, Ying Shen1,2
1State Key Laboratory of Advanced Drug Delivery and Release Systems & Innovation Institute for Artificial Intelligence in Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Abstract:
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.
Insights
T-cell engagers (TCEs) show promise but face safety challenges in solid tumors. This review systematically analyzes TCE design strategies to balance antitumor activity and safety for improved immunotherapeutics.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- T-cell engagers (TCEs) are potent immunotherapeutics with significant clinical efficacy in various cancers.
- Balancing the antitumor activity and safety profile of TCEs, especially in solid tumors, remains a critical challenge.
- Current molecular design strategies often optimize activity and toxicity independently, limiting therapeutic potential.
Purpose of the Study:
- To systematically analyze principal TCE design strategies, evaluating their strengths, limitations, and interdependencies.
- To provide a holistic framework for navigating the activity-safety trade-off in TCE development.
- To guide the development of next-generation TCEs by integrating mechanistic insights.
Main Methods:
- Categorization of TCE strategies into T-cell interface and tumor cell-directed approaches.
- Review of T-cell focused strategies: anti-CD3 affinity tuning, costimulatory signals, and immunosuppressive pathway blockade.
- Examination of tumor-focused strategies: antigen selection, binding valency, and tumor microenvironment (TME)-responsive activation.
Main Results:
- TCE strategies can be broadly classified based on their targeting interface (T-cell or tumor cell).
- T-cell interface strategies aim for spatiotemporal control of T-cell activation.
- Tumor cell-directed strategies focus on enhancing tumor-selective cytotoxicity through antigen targeting and TME responsiveness.
Conclusions:
- Sophisticated TCE formats allow nuanced functional modulation, but deeper mechanistic understanding is crucial.
- Integrating insights into T-cell activation and TME biology is essential for developing safer and more effective TCEs.
- A systematic comparison of existing strategies offers a framework for optimizing TCE design and improving therapeutic outcomes.
Related Concept Videos
01:22T Cell Activation and Clonal Selection
Naive T cells that have not yet encountered an antigen express two primary CD...
01:24B Cell Activation and Differentiation
When naive B cells encounter a specific antigen that can bind to the B cell receptor (BCR) on their surface, they undergo sensitization to respond to the antigen's presence. Sensitization begins with...