Most Cancers Lack a Microbiome — But Gut Tumors Host Complex Microbial Communities

The tumor microbiome has attracted enormous scientific interest, yet conflicting published reports have left fundamental questions unresolved: Do most solid tumors actually harbor microorganisms, or are reported signals largely contamination artifacts? This large-scale, methodologically rigorous study was designed to settle those questions.

The team developed and benchmarked a multi-step bioinformatics pipeline for host-sequence subtraction and microbial classification, then applied it to 16,369 high-depth tumor whole-genome sequencing datasets from the UK 100,000 Genomes Project — one of the largest such analyses to date. The pipeline was validated through in vitro microbe-host mixture experiments and in silico simulations to establish detection thresholds and contamination baselines.

The headline finding is striking in its restraint: after thorough decontamination, the vast majority of cancer types showed microbial signals that were statistically indistinguishable from background contamination. This directly challenges earlier pan-cancer claims of widespread tumor-associated microbiomes across tissues like breast, lung, and brain. The study suggests many prior positive findings may have been driven by insufficient decontamination.

In sharp contrast, orodigestive cancers — those of the mouth, esophagus, stomach, and colorectum — displayed genuine, reproducible multi-kingdom polymicrobial communities. These communities included bacteria, fungi, viruses, archaea, and in certain cases Trichomonas, an unusual protozoan parasite rarely reported in tumor contexts. Community composition varied meaningfully by tumor anatomical site and histological subtype, confirming biogeographic specificity rather than random colonization.

A particularly important finding was the association between microbial load and tumor mutation burden. Tumors with microsatellite instability (MSI) or mutations in DNA polymerase genes POLE or POLD1 — both of which cause hypermutation — showed significantly elevated microbial colonization across orodigestive cancer types. This correlation raises the possibility that a disrupted mucosal barrier in highly mutated tumors permits greater microbial infiltration, or alternatively, that certain microbes contribute to or co-evolve with the mutational landscape. External validation analyses were performed to corroborate key findings. Caveats include the reliance on sequencing data rather than direct tissue culture, and the inherent challenge of definitively ruling out all contamination sources in any sequencing-based microbiome study.