Metal‐Coordinated NIR‐II Nanoadjuvants with Nanobody Conjugation for Potentiating Immunotherapy by Tumor Metabolism Reprogramming

Abstract Immune checkpoint blockade (ICB) immunotherapy remains hampered by insufficient immunogenicity and a high‐lactate immunosuppressive tumor microenvironment (TME). Herein, a nanobody‐engineered NIR‐II nanoadjuvant with targeting metabolic reprogramming capability is constructed for potentiating NIR‐II photothermal‐ferroptosis immunotherapy. Specifically, the nanoadjuvant (2DG@FS‐Nb) is prepared by metallic iron ion‐mediated coordination self‐assembly of D‐A‐D type NIR‐II molecules and loading of glycolysis inhibitor, 2‐deoxy‐D‐glucose (2DG), followed by modification with aPD‐L1 nanobody (Nb), which can effectively target the immunosuppressive TME and trigger in situ immune checkpoint blockade. The nanoadjuvants responsively release therapeutic components in the acidic TME, enabling the precise tumor location by NIR‐II fluorescence/photoacoustic imaging while initiating NIR‐II photothermal‐ferroptosis therapy. The remarkable NIR‐II photothermal efficiency and elevated glutathione (GSH) depletion further sensitize ferroptosis to induce severe lipid peroxidation, provoking robust immunogenic cell death (ICD) to trigger anti‐tumor immune response. Importantly, the released 2DG markedly inhibits lactate generation through glycolysis obstruction. Decreased lactate efflux remodels the immunosuppressive TME by suppressing M2 macrophage proliferation and downregulating regulatory T cell levels. This work provides a new paradigm for the integration of NIR‐II phototheranostics and lactate metabolism regulation into a single nanoplatform for amplified anti‐tumor immunotherapy combined with ICB therapy.