Microbiome oncolytic virus interactions in cancer: emerging evidence and therapeutic implications for immunotherapy

The tumor microenvironment (TME) is essential for the regulation of tumor progression, immune responses, and therapeutic outcomes. The importance of the tumor microbiome, a complex ecosystem of microorganisms that reside within the TME, in shaping tumor dynamics and modulating treatment responses has been underscored by recent advancements in cancer research. Oncolytic viruses (OVs) have been recognized as promising treatment options in cancer immunotherapy due to their ability to selectively target and eliminate tumor cells while protecting normal tissue. Recent preclinical studies suggest a bidirectional relationship between OVs and the microbiome, although direct evidence that OVs remodel tumor-resident microbial communities remains limited. Most available data concern the gut microbiome, where OV treatment has been associated with changes in microbial composition, while baseline or experimentally manipulated microbiota can, in turn, influence virotherapy efficacy. This review examines these emerging interactions, distinguishes direct experimental evidence from proposed mechanisms, and discusses how microbiome-informed strategies may complement OV-based immunotherapy. We also highlight the scarcity of longitudinal intratumoral and clinical microbiome data and identify the experimental steps required to establish causality.