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. 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. A supramolecular bispecific-cell-engager (Supra-BiCE) that simultaneously targets TIGIT on NK/T cells and PD-L1 on tumor cells is fabricated by co-assembly of two immune checkpoint blocking peptides. Supra-BiCE creates artificial connections between NK/T cells with tumor cells as well as blocking both check points, thus increasing infiltration and activation of NK and T cells at tumor site and boosting tumor inhibition rate.image