Programmable Chimeric Antigen Receptor T Cell Circuits With DNA Computing for Precision Tumor Therapy

ABSTRACT Chimeric antigen receptor (CAR) T cells, a promising cancer therapeutics, still face challenges in safety and efficacy due to the incapability to precisely regulate T cell activation. Here we develop a DNA‐logic CAR (DL‐CAR) system that enables programmable targeting and precise ablation of tumors with specific antigen combination patterns. The DL‐CAR system is engineered using HaloTag as an extracellular domain for DNA conjugation, which allows controlling the assembly of tumor‐targeting aptamers for universal and combinatorial antigen recognition via DNA logic computation. DL‐CAR‐T cells are shown to be capable of targeting tumor cells with different antigens and controlling the CAR circuit through AND, OR, and INHIBIT Boolean logic for specific T‐cell activation and cytolysis. The DL‐CAR system demonstrated high efficacy for tumor eradication in mouse models, with the AND‐, OR‐, and INHIBIT‐gated computation affording enhanced selectivity for tumors with specific antigen combinations. DL‐CAR may provide a new paradigm to develop programmable CAR‐T circuits for precision cancer therapy.