Biomimetic nanomodulator reprograms glycolysis-driven immunosuppressive microenvironment to potentiate photothermal immunotherapy in cold tumors

Aberrant glycolytic metabolic reprogramming and intrinsic low immunogenicity in "cold" tumors create a hostile immunosuppressive tumor microenvironment (ITME), severely impairing antitumor immunity. Herein, we designed a biomimetic dual-targeting nanomodulator (CM-cRGD@PBG), using mesoporous polydopamine (mPDA) nanoparticles camouflaged with cRGD-modified Cancer cell membranes. This multifunctional nanomedicine synchronizes metabolic intervention with cellular immune remodeling to dismantle the ITME. Specifically, the delivered GLUT1 Inhibitor BAY-876 reverses lactate-driven immunosuppression by inhibiting M2-like macrophage polarization and regulatory T cell (Treg) expansion. Complementarily, gemcitabine (GEM) is repurposed as a potent immunomodulatory agent to selectively deplete myeloid-derived suppressor cells (MDSCs) and Tregs. Notably, mPDA-mediated photothermal therapy elicits immunogenic cell death (ICD), acting as an in situ nanovaccine that facilitates dendritic cell maturation and antigen presentation. Pancreatic and lung Cancer mouse models demonstrate that this "metabolism-chemotherapy-photothermal" strategy exhibits excellent tumor growth inhibition and successfully converts "cold" tumors into "hot" ones, significantly enhancing cytotoxic T lymphocyte (CTL) infiltration and effector function. Our study offers a universal metabolic and immune modulation strategy for "cold" tumors.