“Internal Trouble and Outside Aggression” Strategy: Energy Deprivation Synergized With cGAS‐STING Pathway Activation for Stimuli‐Responsive Photodynamic‐Metal‐Metabolic Immunotherapy

Abstract The aberrant metabolic activities of tumor cells not only facilitate tumor proliferation but also impair immune cell function and cause an immunosuppressive tumor microenvironment (TME). Thus, reshaping the metabolic TME while activating innate immunity is highly desirable but challenging. Herein, a multifunctional immunomodulator is engineered for near‐infrared light (NIR)‐triggered photodynamic‐metal‐metabolic immunotherapy via the “internal trouble and outside aggression” strategy. Specifically, an endogenous and exogenous stimuli‐responsive nanoagent is prepared consisting of photosensitizer chlorin e6 (Ce6) modified dense silica‐coated rare earth‐doped nanoparticles (ReNPs@SiO 2 (Ce6)), with in situ grown ZIF‐8 on the surface for loading glucose transporter‐1 (GLUT‐1) inhibitor Fasentin and glutaminase‐1 inhibitor bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl)ethyl sulfide (BPTES). The as‐obtained final product is denoted as ReSZ(FB). ReSZ(FB) induces‐ mitochondrial damage and releases mitochondrial DNA (mtDNA) via NIR‐mediated PDT. Subsequently, Zn 2+ from ZIF‐8 collaborates with mtDNA to activate the cGAS‐STING pathway, initiating a robust tumor‐specific immune response. Concurrently, Fasentin and BPTES triggeres energy deprivation by blocking glucose uptake and inhibiting glutamine decomposition, thereby reprogramming the metabolic TME, and alleviating immunosuppression. Tumor cells are damaged and trapped into “internal trouble” by combining PDT and energy deprivation, while the sharply enhanced immune cell lethality exposes cancer cells to “outside aggression”. Overall, this photodynamic‐metal‐metabolic immunotherapy provides a promising paradigm for cancer therapy.