Across the Social Network of the Gut: Bacterial, Fungal, and Viral Determinants of Checkpoint Inhibitor Efficacy and Toxicity.

Recent findings suggest that the gut microbiome significantly influences cancer outcomes, including responses to immune checkpoint inhibitor (ICI) treatments. Although early research focused on gut bacteria, it is now understood that the microbiome includes a bacteriome, virome, and mycobiome, all of which can modulate host immunity. Some commensal bacteria enhance anti-tumor immune responses and improve ICI efficacy, as demonstrated in both mice and patients. Fecal microbiota transplants (FMT) from patients responding to ICI have successfully reversed resistance in certain non-responders. In addition to bacteria, gut fungi and viruses are gaining attention as further factors influencing ICI effectiveness and toxicity. Recent multi-omics studies across cancer cohorts show that fungal and viral populations in the gut vary between ICI responders and non-responders. Commensal fungi may shape anti-cancer immunity by inducing inflammatory or tolerogenic pathways, while viral components can stimulate innate immune sensors that promote tumor surveillance. On the other hand, gut dysbiosis marked by expansion of pathobionts (including opportunistic fungi) and reduction in beneficial microbes is linked to serious immune-related adverse events (irAEs) such as ICI-induced colitis. This review discusses the multi-kingdom gut microbiome-bacteria, fungi, and viruses-and their interactions with the immune system in cancer therapy. We emphasize known mechanisms linking these microbes to anti-tumor immunity, overview human studies associating gut microbiome profiles with ICI outcomes and explore strategies to modulate the microbiome to enhance ICI efficacy while reducing toxicity. Understanding and utilizing the gut mycobiome and virome in conjunction with the bacteriome could pave the way for new biomarkers and therapeutic adjuvants in cancer immunotherapy.