The mycobiome, virome and archaeome in gastrointestinal cancers: molecular pathogenesis and therapeutic intervention

Gastrointestinal (GI) cancers remain a significant global health challenge. For decades, research has concentrated on the bacterial microbiome's role in tumour development, largely neglecting the important roles of the non-bacterial kingdoms, including mycobiome (fungi), the virome (viruses), and archaeome (archaea). These elements represent an underexplored and crucial "dark matter" of the microbiome. This review aims to systematically summarize current evidence on the compositional alterations of viruses, fungi, and archaea across the major types of GI cancer, including colorectal, hepatocellular, gastric, pancreatic and esophageal/oral cancers. We critically examine how viruses, fungi, and archaea directly affect host cellular processes and indirectly influence cancer risk through complex cross-kingdom interactions with the bacterial microbiota and the host immune system. Additionally, we explore the significant translational potential of this knowledge, emphasizing opportunities to use these non-bacterial communities in developing new diagnostic biomarkers and therapeutic strategies. Finally, we highlight the importance of future multi-kingdom integrative analyses to fully understand the microbial ecosystem involved in GI oncogenesis and to translate these insights into clinical practice.