A Transformable Supramolecular Bispecific Cell Engager for Augmenting Natural Killer and T Cell‐Based Cancer Immunotherapy

Abstract Immune cells are pivotal in cancer immunotherapy, yet their therapeutic effectiveness is often hampered by limited tumor infiltration and inhibitory tumor microenvironments. An alkaline phosphatase (ALP)‐responsive and transformable supramolecular bis‐specific cell engager (Supra‐BiCE) to harness natural killer (NK)/T cells for effective cancer immunotherapy is introduced here. The Supra‐BiCE, consisting of both SA‐P (a phosphorylated peptide targeting and blocking programmed cell death ligand 1 (PD‐L1)) and SA‐T (a phosphorylated peptide targeting and blocking T cell immunoglobulin and ITIM domain (TIGIT)) is constructed by a simple co‐assembling strategy. Upon intravenous administration, Supra‐BiCE self‐assembles into nanoribbons and interacts with NK/T cells via TIGIT. Notably, these nanoribbons undergo transformation into long nanofibrils within ALP‐overexpressing tumor regions, resulting in enhanced binding affinities of Supra‐BiCE to both PD‐L1 and TIGIT. Consequently, this leads to the accumulation and retention of NK/T cells within tumor regions. Furthermore, the combinatorial blockade of checkpoints by Supra‐BiCE activates infiltrating NK/T cells. Moreover, the adjustable peptide ratio in Supra‐BiCE enables customization for optimal therapeutic effects against distinct tumor types. Particularly, Supra‐BiCE (T:P = 1:3) achieved 98.27% tumor suppression rate against colon carcinoma model. Overall, this study offers a promising tool for engaging NK and T cells for cancer immunotherapy.