By Allison Proffitt
July 8, 2025 | Researchers at the University of Chicago have published a new approach to cancer detection offering early unprecedented accuracy in identifying both early and late-stage cancers through a simple blood plasma test. The results were published today in a Brief Communication in Nature Biotechnology (DOI: 10.1038/s41587-025-02731-8).
Chuan He, senior author on the paper and the John T. Wilson Distinguished Service Professor of Chemistry and Professor of Biochemistry and Molecular Biology at UChicago, said the work emerged from explorations during the COVID-19 pandemic. His lab had been working on cell-free DNA diagnostics for colon cancer in conjunction with Marc Bissonnette, University of Chicago Department of Medicine, for years. During the pandemic, they set out to study RNA. While their investigation into long RNA fragments proved disappointing due to degradation by nucleases, they discovered something remarkable: short RNA fragments, particularly transfer RNAs (tRNAs), remained intact and detectable in blood plasma.
“To our surprise, we realized the wide majority of these RNAs come from the host, but about 20%-30% come from the microbiome,” He told Diagnostics World News. This observation led to a crucial finding: while host-derived short RNAs showed little differentiation between cancer patients and healthy controls, microbiome-derived tRNAs provided reasonable separation, achieving 60%-70%.
As a next step, the team applied modification sequencing to these microbiome RNAs. Drawing from their previous work in plant biology, they knew that RNA modifications serve as indicators of cellular activity. They developed low-input multiple methylation sequencing (LIME-seq), a scaled-down sequencing protocol specifically designed to handle the small amounts of cell-free RNA found in blood samples. “This method enables simultaneous detection of site-specific RNA modifications… across multiple RNA species in ultralow-input cfRNAs while also monitoring stoichiometry changes of these modifications,” the authors explain in the paper.
(He particularly highlighted the contributions of first author Cheng-Wei Ju, the University of Chicago, Bissonnette, and Li-Sheng Zhang, The Hong Kong University of Science and Technology, in making the work possible.)
The results, He says, were “exceptional”. Using RNA modifications as biomarkers, the team achieved an area under the curve (AUC) of over 95% for both early and late-stage colorectal cancer detection. Most remarkably, they identified four out of five stage-zero cancer cases—a level of early detection accuracy that He says may be unprecedented, though of course the sample size is quite small.
Faster Death, Easier Detection
The method works because bacterial turnover is naturally rapid—microbes have shorter lifespans than human cells and are continuously dying and releasing their contents into the bloodstream. When these microbes become active in response to disease conditions, both their turnover rate and modification levels increase, creating a detectable signal in blood plasma.
The research represents what He calls “a completely new direction, never being thought of, never being realized,” offering a direct readout of host-microbe interactions from human blood and their correlation with human diseases. He identified three key factors that make their approach so effective:
- Rapid Microbial Response: Microbes respond quickly to changes in host conditions, including inflammation and physiological changes associated with cancer. Their rapid turnover means dying microbes continuously release RNA into the bloodstream—far earlier than dying tumor cells would release cell free DNA.
- Modification as Activity Indicator: RNA modifications, particularly in ribosomal RNAs, directly correlate with microbial activity levels. Active microbes have higher modification levels, while dormant ones have lower levels, providing a clear readout of microbial response to host conditions.
- Consistency Across Samples: Unlike RNA abundance, which can vary dramatically based on collection conditions and timing, modification levels remain consistent for a given condition. Whether a sample contains 100 or 10,000 copies of a particular RNA, the modification level stays the same, dramatically reducing variability in sample collection and preparation.
Clinical Applications and Future Directions
The team has already tested the method’s effectiveness beyond colorectal cancer, showing promising results in pancreatic cancer samples using the same approach. They are now expanding their studies to include larger cohorts and are particularly focused on early-onset colorectal cancer, which represents a major health challenge.
But He also emphasized the potential applications beyond cancer detection, expecting the approach to be useful, “for most human disease, not just tumors, that have a microbiome in the space that responds to physiological checks.”