Advances in Ligand-based Surface Engineering Strategies for Fine-Tuning T cell Mechanotransduction toward Efficient Immunotherapy.

T cell-based immunotherapy has recently emerged a promising strategy to treat cancer, which requires the activation of antigen-directed cytotoxicity to kill cancer cells. Mechanical signaling, although often overshadowed by its biochemical counterpart, play a crucial role in T cell anti-cancer responses, from activation to cytolytic killing. Rapid advancements in the fields of chemistry, biomaterial, and micro/nanoengineering offer an interdisciplinary approach to incorporate mechano- and immuno-modulatory ligands, including but not limited to synthetic peptides, small molecules, cytokines, artificial antigens, onto the biomaterial-based platforms to modulate mechanotransducive processes in T cells. Surface engineering of these immunomodulatory ligands with optimization of ligand density, geometrical arrangement, and mobility are proven to better mimic natural ligation between immunoreceptor-ligand to directly enhance or inhibit mechanotransduction pathways in T cells, through triggering upstream mechanosensitive channels, adhesion molecules, cytoskeletal components, or downstream mechano-immunological regulators. Despite its tremendous potential, however, current research on this new biomaterial surface engineering approach for mechano-modulatory of T cell activation and effector functions remains in a nascent stage. This review highlights the recent progress in this new direction, focusing on achievements in mechano-modulatory ligand-based surface engineering strategies and underlying principles, and outlooks the further research in the rapidly evolving field of T cell mechanotransduction engineering for efficient immunotherapy.