A Common Gut Fungus May Be Fueling Colorectal Cancer Metastasis

Colorectal cancer is already one of the hardest cancers to treat once it reaches distant organs, with five-year survival rates for stage IV disease sitting around 11 to 14 percent. Now, early-stage research presented at the International Digestive Disease Forum 2026 suggests that a common gut fungus, Candida albicans, may be actively worsening those odds by hijacking immune cells to prepare the lung for incoming tumor cells. The findings are preliminary, drawn from patient samples and mouse models, but they point to a specific molecular chain that could eventually be disrupted with existing drug targets.

Candida albicans colonization is higher in patients with metastatic colorectal cancer

The study, led by D. Liang, H. Li, L. Zhang, and colleagues, began with a straightforward clinical observation: colorectal cancer patients who already had distant metastases showed significantly elevated intestinal colonization by Candida albicans compared with patients whose disease had not spread. That correlation alone does not prove causation, but it motivated the team to ask whether the fungus was a passenger or a driver.

Candida albicans is not exotic. It lives in the gut of most healthy adults as a harmless commensal, kept in check by the bacterial microbiota. When that balance is disrupted, through antibiotics, illness, or immune suppression, the fungus can shift from harmless resident to opportunistic pathogen. Prior work has shown that C. albicans activates pro-metastatic signaling pathways including MAPK and NF-kB, and a broader body of research has implicated it in mucosal damage, carcinogen production, and chronic inflammation that may favor tumor growth. This new study adds a sharper mechanistic picture to that literature.

Candidalysin toxin drives a macrophage-neutrophil chain that seeds the lung

The central finding involves a fungal toxin called candidalysin, encoded by the ece1 gene. When the researchers gave mice oral doses of wild-type C. albicans or injected candidalysin intraperitoneally, metastatic burden in the lungs increased. Crucially, when they used an ece1-deficient strain of the fungus, one that cannot produce candidalysin, the pro-metastatic effect was substantially attenuated. The toxin, not the fungus itself, appears to be the key agent.

Single-cell RNA sequencing of lung immune cells revealed what candidalysin was doing: it drove an increase in neutrophils displaying a neutrophil extracellular trap, or NET, formation phenotype. NETs are web-like structures that neutrophils release, originally evolved to ensnare pathogens, but here appearing to create a physical scaffold that helps tumor cells establish themselves in the lung.

The sequence the team mapped runs as follows. Candidalysin activates the CARD9 signaling pathway inside macrophages. CARD9 then triggers NF-kB, which upregulates expression of the chemokine CCL6. Elevated CCL6 recruits neutrophils to the lung via the CCR1 receptor on their surface. Those neutrophils then form NETs, which constitute the pro-metastatic niche. Macrophages and neutrophils are known to enhance tumor cell invasion through their crosstalk in the microenvironment, but identifying a specific fungal trigger for that crosstalk is a new contribution.

How the team confirmed each link in the chain

The researchers stress-tested this pathway at multiple points. Depleting macrophages attenuated the metastatic promotion; so did depleting neutrophils, confirming that both cell types are required, not just one. Using macrophage-specific CARD9 knockout mice removed the signaling link between candidalysin and CCL6 production, blocking downstream neutrophil recruitment. Transcriptomic sequencing confirmed that candidalysin activates NF-kB through CARD9 and that this activation is the upstream event driving CCL6 upregulation.

Critically, the team also tested two disruption strategies aimed at the downstream end of the pathway. Administering DNaseI, an enzyme that degrades DNA-based NET structures, reduced the pro-metastatic effect. So did pharmacological CCR1 antagonism, which blocks neutrophil recruitment to the lung by interfering with the CCL6 signal. Both interventions leave the fungus and the macrophage response intact but interrupt the chain before it can construct a metastatic niche.

Caveats and open questions about this C. albicans mechanism

Several important limitations apply. This is a conference abstract, not a peer-reviewed full paper, meaning the complete dataset and statistical analyses are not yet publicly available. The patient data are correlational: the study cannot rule out that sicker patients, who are more likely to have metastases, are also more susceptible to Candida overgrowth for independent reasons. Mouse metastasis models, while useful for mechanism hunting, do not always translate to human disease.

The role of CCL6 specifically also warrants scrutiny. CCL6 is a mouse chemokine; its human functional equivalent and whether the same axis operates identically in human tissue is a question the abstract does not resolve. Approximately 2 in 10 colorectal cancer cases in the United States are already diagnosed at a distant stage, meaning the population that could be affected by a fungal accelerant is substantial, which makes rigorous follow-up essential rather than optional.

Potential therapeutic targets in the CARD9-CCL6-NET pathway

If the mechanism holds up in further study, the pathway offers at least three candidate intervention points: antifungal therapy to reduce C. albicans load in high-risk patients, CCR1 antagonists to block neutrophil recruitment, and NET-disrupting agents like DNaseI or related compounds. None of these is ready for clinical application based on this work alone, and the challenge of drug-resistant Candida strains adds another layer of complexity to any antifungal strategy.

What the study does establish, at least provisionally, is that the gut mycobiome, the fungal component of the microbiome, deserves more attention in colorectal cancer research. Bacterial microbiome studies in CRC are now abundant, but fungal contributions have received far less scrutiny. A toxin-specific mechanism involving a common commensal, a defined signaling axis, and two druggable endpoints makes this a credible candidate for follow-up trials. The next step will be replicating the human colonization data in a larger, prospectively designed cohort and confirming whether the CCL6 axis operates in human macrophages the same way it does in mice.

Evidence rating

INVESTIGATIONAL — 73/100

Caveats:

• The majority of mechanistic findings come from mouse models and cell culture experiments, not controlled human trials.
• This is a conference abstract presented at DDW 2026 and has not yet undergone full peer review as a complete manuscript.
• The human component is observational — elevated C. albicans colonization was associated with metastatic CRC, but causation has not been established in people.
• Funding source was not disclosed, so independent verification of this work has not been confirmed.

Conference abstract combining a small observational human cohort with mouse model and in vitro experiments. The human data show an association between C. albicans colonization and metastatic CRC but cannot establish causation. Mechanistic findings are derived primarily from animal models and cell culture, and the work has not yet been published as a full peer-reviewed manuscript or independently replicated.

References

1. Dayi Liang (2026). Tu1321 CANDIDA ALBICANS ACCELERATES COLORECTAL CANCER METASTASIS VIA MACROPHAGE-NEUTROPHIL INTERPLAY. Gastroenterology. https://doi.org/10.1016/s0016-5085(26)01215-1
2. Mohammed Iyoob Mohammed Ilyas (2023). Epidemiology of Stage IV Colorectal Cancer: Trends in the Incidence, Prevalence, Age Distribution, and Impact on Life Span. Clinics in Colon and Rectal Surgery. https://doi.org/10.1055/s-0043-1761447
3. Candida albicans drives colorectal cancer progression by inducing hypoxia signaling – eLife. elifesciences.org. https://elifesciences.org/articles/93510
4. Dalang Yu, Zhiping Liu (2022). The research progress in the interaction between Candida albicans and cancers. Frontiers in Microbiology. https://doi.org/10.3389/fmicb.2022.988734
5. Irene Di Ceglie, Silvia Carnevale, Anna Rigatelli, Giovanna Grieco, Piera Molisso, Sebastien Jaillon (2024). Immune cell networking in solid tumors: focus on macrophages and neutrophils. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2024.1341390
6. U.S. Cancer Statistics Colorectal Cancer Stat Bite – CDC. cdc.gov. https://www.cdc.gov/cancer/colorectal/statistics/statbite/index.htm
7. Yang Gao, Qinyan Cao, Yuyang Xiao, et al. (2024). The progress and future of the treatment of Candida albicans infections based on nanotechnology. Journal of Nanobiotechnology. https://doi.org/10.1186/s12951-024-02841-6