Remodeling Tumor Metabolism via Self‐Amplifying Energy‐Depleting Nanocomplexes for Effective Photodynamic‐Immunotherapy

Abstract The abnormal metabolism of tumor cells fulfills their high energy demands for rapid growth while simultaneously reshaping the tumor microenvironment (TME), which suppresses immune cell function and facilitates immune evasion. Herein, a peptide‐based nanocomplex (DCK@siGLUT1) that synergizes with photodynamic therapy (PDT) to disrupt tumor cell energy metabolism is developed. DCK@siGLUT1, utilizing a mitochondria‐targeting peptide (dKLA) selectively accumulates in mitochondria, where it impairs mitochondrial membrane integrity, disrupts energy metabolism, and induces apoptosis. Upon apoptosis, activated caspase‐3 (Casp3) cleaves DCK@siGLUT1, releasing siGLUT1 to silence glucose transporter 1 (GLUT1) expression, which further inhibits glucose uptake and intensifies metabolic collapse, thereby amplifying apoptotic effects. Moreover, Ce6, conjugated to dKLA, is co‐delivered to the mitochondria and, upon light activation, exacerbates mitochondrial damage and metabolic disruption. These combined mechanisms intensify oxidative stress and apoptosis, further activate Casp3, and promote DCK@siGLUT1 cleavage, thereby driving a self‐amplifying tumoricidal cascade. Furthermore, DCK@siGLUT1 effectively induces immunogenic cell death (ICD), triggers antitumor immune responses, and inhibits both primary and distant tumor growth and metastasis. This strategy offers a novel approach for targeting tumor energy metabolism in antitumor immunotherapy.