Harnessing phages in the age of antibiotic resistance: immunological perspectives.

The rapid rise of antimicrobial resistance (AMR) has renewed interest in bacteriophages as precision antibacterial agents that can selectively target pathogenic bacteria while limiting disruption of commensal microbiota. However, therapeutic phages are not immunologically inert. Phage particles, phage-derived nucleic acids, bacterial lysis products, and manufacturing impurities can interact with innate and adaptive immune pathways, influencing phage pharmacokinetics, tissue persistence, inflammatory responses, and treatment durability. Innate mechanisms such as complement activation, phagocyte uptake, pattern-recognition receptor signaling, and neutrophil-mediated antibacterial responses may either restrict phage bioavailability or support bacterial clearance. Adaptive immune responses, particularly anti-phage antibodies and serum neutralization, may become relevant during repeated or systemic administration, although available clinical evidence indicates that antibody development does not uniformly predict treatment failure. This review integrates mechanistic, translational, and clinical evidence on phage-immune interactions, distinguishing direct immune recognition of phage components from indirect immune activation mediated by bacteria and bacterial products. We also discuss immune-aware strategies, including phage selection, formulation, route optimization, product-quality control, and immune monitoring, to improve the development of phage therapies for multidrug-resistant bacterial infections.