Engaging T cells for cleanup

Roman Mungalov^1,2,3Natalia V Mushenkova^2,4Dmitriy M Chudakov^1,2,5,6,7*Maria A Turchaninova^1,2

• ¹Research Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Moscow Oblast, Russia
• ²Institute of Bioorganic Chemistry (RAS), Moscow, Moscow Oblast, Russia
• ³Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, Moscow, Moscow Oblast, Russia
• ⁴Russia Unicorn Capital Partners, Moscow, Russia
• ⁵Center for Molecular and Cellular Biology, Moscow, Moscow Oblast, Russia
• ⁶Central European Institute of Technology (CEITEC), Brno, Olomouc, Czechia
• ⁷Abu Dhabi Stem Cells Center (ADSCC), Abu Dhabi, United Arab Emirates

T-cell engagers represent a transformative approach to cancer immunotherapy leveraging bispecific and multispecific antibody constructs to redirect T-cell cytotoxicity toward malignant cells. These molecules bridge T cells and tumor cells by simultaneously binding CD3 on T cells and tumor-associated antigens on cancer cells, thereby enabling precise immune targeting even in immunologically "cold" tumors. Recent advancements include conditional T-cell engagers activated by tumor microenvironment proteases to minimize off-tumor toxicity as well as T-cell receptor-based engagers targeting intracellular antigens via MHC presentation. Clinical successes, such as Kimmtrak in metastatic uveal melanoma, underscore good potential of these modalities, while challenges persist in the management of cytokine release syndrome, neurotoxicity, and tumor resistance. Emerging multispecific engagers are aimed at enhancing efficacy via incorporation of costimulatory signals, thus offering a promising trajectory for next-generation immunotherapies. T-cell engagers are also gaining attention in the treatment of autoimmune disorders, where they can be designed to selectively modulate pathogenic immune responses. By targeting autoreactive T or B cells, T-cell engagers hold promise for restoring immune tolerance in such conditions as HLA-B*27-associated autoimmunity subtypes, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus. Engineering strategies that incorporate inhibitory receptors or tissue-specific antigens may further refine T-cell engagers' therapeutic potential, by minimizing systemic immunosuppression while preserving immune homeostasis.