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

Immune cells are pivotal in cancer immunotherapy, yet their therapeutic effectiveness is often hampered by limited tumor infiltration and inhibitory tumor microenvironments. We here introduce an alkaline phosphatase (ALP)-responsive and transformable supramolecular bis-specific cell engager (Supra-BiCE) to harness NK/T cells for effective cancer immunotherapy. The Supra-BiCE, consisting of both SA-P (a phosphorylated peptide targeting and blocking PD-L1) and SA-T (a phosphorylated peptide targeting and blocking 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 cells and CD8 + T cells within tumor regions. Furthermore, the combinatorial blockade of checkpoints by Supra-BiCE activates infiltrating NK/T cells, as evidenced by upregulated expression of perforin, granzyme B, TNF-a, and IL-2. 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 CT26 cell tumor model. Overall, our study offers a promising tool for engaging NK and T cells for cancer immunotherapy. This article is protected by copyright. All rights reserved.