Engineered Bacteria-Nanoparticle Conjugate Reprograms Immunosuppressive Niche via Dendritic Cell-Centric Innate-Adaptive Immune Coupling.

Abstract

The immunosuppressive tumor microenvironment (TME) represents a critical barrier to effective T cell activation, contributing to immunotherapy resistance. Dendritic cells (DCs), essential initiators of T cell-mediated adaptive immunity, frequently display both quantitative defects and functional impairments within the TME. Compounding this challenge, emerging evidence highlights the indispensable role of innate immunity in sustaining T cell activity and establishing durable immunological memory. To address these limitations, we engineered M-CHNP/D: a bacteria-nanoparticle hybrid platform integrating <i>Escherichia coli</i> with acid-responsive calcium carbonate nanoparticles encapsulating the programmed cell death ligand-1 blocking peptide ^DPPA-1. Leveraging the motility and targeting capabilities of bacteria, M-CHNP/D achieves a deep tumor penetration and neutralizes the acidic TME. M-CHNP/D induced tumor-cell-derived CCL3 upregulation, driving DC recruitment and spatial redistribution within the tumor parenchyma. This intervention enhanced DCs' antigen-presenting capacity, ultimately potentiating adaptive immune responses. Furthermore, M-CHNP/D administration significantly increased the population of innate immune cells and induced their phenotypic reprogramming toward antitumor functional states. By reshaping the immune "hot" network, M-CHNP/D combined with radiotherapy effectively inhibited tumor growth and recurrence. M-CHNP/D demonstrates significant potential in modulating both innate and adaptive immunity, offering a robust strategy for improving cancer immunotherapy outcomes.