Tumor Topography Remodels TME Signalling via Compartment-Specific Host–Microbiome–Tumor Crosstalk in Hepatoblastoma

Abstract

Simple Summary Tumors develop within a complex microenvironment shaped by signals from cancer cells, host tissues, and the microbiome. We combined bacterial and archaeal profiling with host and tumor (xenograft) transcriptomes in orthotopic versus ectopic hepatoblastoma models to examine how tumor location relates to signaling programs in the tumor microenvironment (TME). Using pathway-level analyses and multi-omics integration, we observed compartment-specific differences in key signaling axes, including TNFA/NF-κB, hypoxia, the unfolded protein response, xenobiotic metabolism, mTORC1, KRAS, epithelial–mesenchymal transition, and MYC/E2F cell-cycle programs. Archaea showed pronounced, niche-specific signatures that correlated positively with proliferative and inflammatory pathways and negatively with interferon responses. These results provide a compartment-resolved map of host–microbiome–tumor crosstalk at the signaling level and generate hypotheses for modulating TME signaling through interkingdom interactions.