Innate immune recognition and immunomodulatory effects of bacteriophages: implications for phage therapy

Bacteriophages (phages) have been explored as a potential treatment for infectious diseases owing to their bacteriolytic ability. However, accumulating evidence indicates that phages interact with the host immune system and modulate innate immune responses. Phage particles, genomes, and phage-derived components are sensed by pattern recognition receptors, including Toll-like receptors and cytosolic nucleic acid sensors, leading to context-dependent activation or suppression of inflammatory signaling pathways, such as nuclear factor κ-light-chain-enhancer of activated B cells and type I interferon responses. In clinical settings and in vivo experiments, phage-induced immunomodulation influences infection outcomes by promoting bacterial clearance, limiting excessive inflammation, and facilitating tissue repair. However, phage-mediated immune regulation is not uniformly beneficial and may impair antibacterial immunity or exacerbate inflammatory diseases in certain contexts. In this review, we summarize current knowledge of phage innate immune recognition, the immunomodulatory effects in infectious and inflammatory settings, and the implications of these interactions for the safety and efficacy of phage therapy. A deeper understanding of phage-immune system interactions is essential for optimizing phage selection and administration. This knowledge can facilitate the development of combination therapies tailored to the host immune status and specific disease contexts.