Tumor-Tropic Bacterial-Nanoparticle Hybrids for Metabolic Reprogramming and Cancer Immunotherapy.

Abstract

Metabolic dysregulation and immune suppression are intrinsically linked within the solid tumor microenvironment, yet effective strategies to simultaneously reprogram tumor metabolism and restore antitumor immunity remain challenging. Here, we present a tumor-tropic bacterial-nanoparticle hybrid (SW@CDFM) that integrates metabolic reprogramming with immune activation for synergistic cancer treatment. The designed biohybrid system is constructed by covalently conjugating <i>Shewanella oneidensis</i> bacteria with tumor cell membrane-camouflaged DOX-Fe/CpG nanoparticles. Leveraging the intrinsic hypoxia tropism of <i>Shewanella</i>, SW@CDFM selectively accumulates in tumors, alleviates lactate-driven acidosis, and remodels the metabolic landscape of the tumor microenvironment. Concurrently, pH-responsive release of doxorubicin and CpG induces immunogenic cell death and activates dendritic cells, initiating a coordinated innate-to-adaptive immune cascade characterized by macrophage repolarization and robust cytotoxic T-cell infiltration. When combined with αPD-1 checkpoint blockade, SW@CDFM achieves more than 90% tumor growth inhibition in murine models and effectively converts immunologically "cold" tumors into "hot" ones. This work establishes a paradigm for the rational design of biohybrid systems that synergize microbial therapy with nanotechnology to surmount biological barriers in cancer treatment.