A biomimetic SPARC platform coupling adaptor recruitment and BRS-Lck condensation for enhanced NK/T cell combination therapy

Abstract

Immune cell engineering has proven to be a promising therapeutic strategy for cancers and autoimmune diseases. Compared to classical CAR therapies, engineered T cells with modified TCRs (such as STAR-T and TRuC-T) exhibit lower tonic signaling and higher persistence. Inspired by this, we developed novel Synthetic Parallel Antigen Receptor Complexes (SPARC) based on the NK cell receptor 1 (NCR1) and the TCR chain. These SPARCs can recognize target cells via engineered extracellular domains and transduce signals by recruiting endogenous adaptor proteins (CD3{zeta}/FcR{gamma}). In NK cells,SPARCs confer high antigen specificity against lymphoma and enables NK cells to specifically recognize and kill tumor cells. Mechanistically, the cytoplasmic domain of NCR1 forms condensates with Lck kinase through two conserved basic-rich sequences (BRS), thereby promoting receptor clustering and enhancing NK cell cytotoxicity. Our findings indicate that SPARCs can also be applied to other immune cells expressing CD3{zeta} and FcR{gamma}. Incorporation of costimulatory domains further improves the performance of SPARCs. Furthermore, combining SPARC-engineered T cells and NK cells showed superior efficacy compared to either cell type alone. This biomimetic design preserves low basal signaling, overcomes the recognition limitations of endogenous receptors, and provides a versatile platform for engineering other membrane complexes.