Bacteriophages as emerging modulators of antitumor immunity in the tumor microenvironment

The tumor microenvironment (TME) is increasingly recognized as a complex ecosystem shaped by dynamic interactions among tumor cells, immune cells, and microbial components. While growing evidence has established the microbiota as a key regulator of antitumor immunity and immunotherapy response, the contribution of bacteriophages, the most abundant biological entities within microbial communities, has remained largely overlooked. Recent studies suggest that bacteriophages are not merely passive regulators of bacterial populations but can actively modulate host immune responses and influence tumor-associated immune landscapes. In this review, we summarize emerging evidence suggesting that bacteriophages may influence antitumor immunity through both direct and indirect mechanisms. Evidence from immune-cell and non-cancer experimental systems indicates that phage nucleic acids can engage TLR9-dependent sensing and, for selected phages, STING-associated inflammatory signaling; however, the relevance of these pathways within human tumors remains to be established. Indirectly, phages may alter microbial community structure and metabolic outputs, which could influence systemic immune tone and the composition of immune infiltrates within the TME. We further discuss accumulating data linking phageome features with tumor progression and responses to immune checkpoint blockade and other cancer therapies. However, much of the available evidence remains preclinical, indirect, or correlative, and causal roles for endogenous phages in human tumor immunity still require further validation. Distinct from the putative ecological and immunological roles of naturally occurring phages, engineered bacteriophages are being developed as therapeutic platforms for cancer immunotherapy, including tumor-antigen display, targeted delivery of immune agonists, cytokines or nucleic acids, and combination strategies with existing treatments. Finally, we address key methodological, mechanistic, and safety challenges that must be overcome to translate phage-based immunomodulation into clinical applications. Collectively, this review highlights the phageome as an emerging regulatory layer of tumor immunity and a promising, yet underexplored, target for therapeutic intervention.