NO-Shielded T Cells for Enhanced Antitumor Immunotherapy

T cell-based immunotherapy relies on the ability of T cells to sustain potent tumor-specific immune responses. However, the immunosuppressive tumor microenvironment (TME) frequently impairs T cell function and survival, limiting therapeutic efficacy. Nitric oxide (NO), which is highly enriched in the TME, contributes to T cell dysfunction through aberrant protein modifications and disruption of intracellular signaling. Here, we developed membrane-fusible NO-scavenging liposomes (LipoNOX) to locally regulate NO levels in T cells exposed to the TME. LipoNOX was formulated with o-phenylenediamine-containing lipids and 1,2-dioleoyl-3-trimethylammonium-propane, enabling efficient incorporation into the T cell plasma membrane. Following membrane integration, LipoNOX reduced NO-mediated protein modifications, including S-nitrosylation and tyrosine nitration. LipoNOX-engineered T cells (NOX-T cells) maintained enhanced proliferation and activation under immunosuppressive TME-mimicking conditions while preserving their physiological properties. These findings demonstrate that engineering T cells with an NO-scavenging membrane platform can alleviate NO-mediated immunosuppression and enhance the antitumor activity of T cell therapy.