Advances in ligand-based surface engineering strategies for fine-tuning T cell mechanotransduction toward efficient immunotherapy.

T cell-based immunotherapy has recently emerged as a promising strategy to treat cancer, requiring the activation of antigen-directed cytotoxicity to eliminate cancer cells. Mechanical signaling, although often overshadowed by its biochemical counterpart, plays a crucial role in T cell anticancer responses, from activation to cytolytic killing. Rapid advancements in the fields of chemistry, biomaterials, and micro/nanoengineering offer an interdisciplinary approach to incorporating mechano- and immunomodulatory ligands, including but not limited to synthetic peptides, small molecules, cytokines, and artificial antigens, onto the biomaterial-based platforms to modulate mechanotransducive processes in T cells. The surface engineering of these immunomodulatory ligands with optimization of ligand density, geometrical arrangement, and mobility has been proven to better mimic the natural ligation between immunoreceptors and ligands to directly enhance or inhibit mechanotransduction pathways in T cells, through triggering upstream mechanosensitive channels, adhesion molecules, cytoskeletal components, or downstream mechanoimmunological regulators. Despite its tremendous potential, current research on this new biomaterial surface engineering approach for mechanomodulatory 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 mechanomodulatory 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.