Cell Surface‐Tethered Nucleic Acid Therapeutics Program Robust and Tumor‐Responsive Enhancement of Adoptive Cell Therapy

Abstract The efficacy of adoptive T cell therapy (ACT) against solid tumors is significantly limited by the immunosuppressive tumor microenvironment (TME). Systemic administration of immunostimulants provides inadequate support to ACT cells and often elicits systemic toxicities. Here we present cell‐surface‐anchored nucleic acid therapeutics (NATs) to robustly enhance ACT through synergistic blockade of immunosuppressive adenosine and PD‐1/PD‐L1 pathways in tumors. Two distinct NATs‐DNA aptamers targeting PD‐L1 (aptPD‐L1) and ATP (aptATP)‐are engineered to form partially‐hybridized duplexes (aptDual) that can efficiently anchor to cell surface before transfer. Backpacked aptDual spatial‐temporally co‐localize with ACT cells in vivo and jointly infiltrate the ATP‐rich TME. Upon binding with ATP, aptDual dissociates to responsively release aptPD‐L1. Concurrently, aptATP scavenges extracellular ATP and its metabolite adenosine to disrupt the inhibitory adenosinergic axis, thereby sensitizing ACT cells to immune checkpoint blockade by aptPD‐L1. This dual inhibition elicited a remarkable 40‐fold increase in functional tumor‐infiltrating ACT cells, substantially boosting the efficacy of TCR‐T and CAR‐T cells in multiple solid tumor models, even in immunologically “cold” tumors. NAT backpacks provide a facile, versatile, and safe strategy to augment various ACTs against solid tumors.