Light-Controlled Bioorthogonal Chemistry Altered Natural Killer Cell Activity for Boosted Adoptive Immunotherapy

Natural killer (NK) cell-based immunotherapy has received much attention in recent years. However, its practical application is still suffering from the decreased function and inadequate infiltration of NK cells in the immunosuppressive microenvironment of solid tumors. Herein, we construct light-responsive porphyrin Fe array-armed NK cells (denoted as NK@p-Fe) for cell behavior modulation via bioorthogonal catalysis. By installing cholesterol-modified porphyrin Fe molecules on the NK cell surface, a catalytic array with light-harvesting capabilities is formed. This functionality transforms NK cells into cellular factories capable of catalyzing the production of active agents in a light-controlled manner. NK@p-Fe can generate the active antineoplastic drug doxorubicin through bioorthogonal reactions to enhance the cytotoxic function of NK cells. Beyond drug synthesis, NK@p-Fe can also bioorthogonally catalyze the production of the FDA-approved immune agonist imiquimod (IMQ). The activated immune agonist plays a dual role, inducing dendritic cell maturation for NK cell activation and reshaping the tumor immunosuppressive microenvironment for NK cell infiltration. This work represents a paradigm for the modulation of adoptive cell behaviors to boost cancer immunotherapy by bioorthogonal catalysis.