Nanobody-enhanced T cell cancer immunotherapy: Advancing precision medicine

Due to their small size, high specificity, and modularity, nanobodies, or single-domain antibodies, have emerged as versatile tools in cancer immunotherapy. This review provides a comprehensive and up-to-date overview of nanobody-based strategies designed to enhance T cell-mediated anti-tumor responses. It first outlines the structural and functional characteristics of nanobodies, highlighting their tumor penetration and modular design potential. Then, three major nanobody-driven therapeutic approaches are discussed in detail: immune checkpoint inhibition, T cell engagement, and chimeric antigen receptor (CAR)-T cell engineering. For each strategy, current preclinical and clinical developments are reviewed. Challenges are explored, along with emerging strategies to overcome them and expand the therapeutic applicability of nanobody-based immunotherapy, including format choice, valency tuning, pharmacokinetic optimization, and safety enhancements.