Space Invaders: Extracellular bacterial occupation alters tumor fate

Our bodies’ mucosal tissues are constantly exposed to bacteria. When tumors form at these sites, such as in colorectal cancer (CRC) and oral squamous cell carcinoma (OSCC), normal epithelial barriers can be disrupted, further increasing bacterial exposure and entry. Imagine these tumors as fortresses whose defenses are down, and bacteria as invaders who breach the walls with little resistance. Once inside, the invaders rearrange the space, exploit the fortress’s own resources, and turn it into a stronghold that resists counterattacks.

Fusobacterium nucleatum (F. nucleatum), a species of anaerobic bacteria normally found in the oral microbiome, has repeatedly been found enriched within tumor tissue compared with adjacent normal tissue. But what is the relationship between these bacteria and their tumor hosts—are these bacteria passively along for the ride? Plotting a hostile takeover? Or are they looking for a mutually beneficial arrangement? While higher tumor burden of F. nucleatum is often linked to more aggressive disease features and worse outcomes, the intricacies of the bacteria-tumor relationship are not well-defined.

In a new study published in Cancer Cell, Dr. Galeano Niño and colleagues in the Bullman Lab—formerly of the Human Biology division at Fred Hutch—revealed how extracellular tumor-infiltrating bacteria, especially F. nucleatum, remodel the tumor microenvironment and contribute to cancer progression.

Using high-resolution imaging and spatial single-cell transcriptomics across patient samples and mouse models, the team mapped bacteria within tumors and found widespread extracellular localization of bacteria in spatially distinct areas called microniches. These microniches are characterized by necrotic tumor tissue, lower cancer cell density, reduced transcriptional activity, and diminished expression of proliferation markers such as Ki-67. In contrast, bacteria-free tumor regions had more densely clustered and actively cycling tumor cells.

“Using functional lentivirus constructs and live-cell confocal imaging, we monitored in real-time cell cycle dynamics of cancer cells exposed to intratumoral bacteria. Our movies have shown that intratumoral bacteria can infiltrate solid masses disrupting the interepithelial tight junctions among cancer cells. The lack of cancer cell attachment disrupts signaling pathways involved in cell proliferation, inducing cell quiescence,” lead author Jorge Galeano Niño explains.

The effect was species-specific, as not all bacteria caused G0-G1 arrest. It is known that F. nucleatum is capable of intracellular infection, so the authors also tested a predominantly non-epithelial-cell-invasive Fusobacterium species, Fusobacterium necrophorum, and observed similar G0-G1 induction. This pinpointed that the effects were due to extracellular bacteria in the tumor microenvironment.

The bacteria’s effects on the tumor were reversible—when bacteria were cleared with antibiotics, cancer cells regained attachment, exited quiescence and resumed cycling. The bacteria-induced quiescent state appeared to provide protection of the tumor from the chemotherapy 5-FU. Once treatment pressure was gone, tumor cells previously exposed to bacteria regenerated larger tumor-like spheroids than uninfected cells. “This novel biological mechanism may explain resistance to chemotherapeutic agents that target active-cycling cancer cells,” Galeano Niño elaborates.

Mouse tumor models corroborated these insights and demonstrated that tumor-infiltrating bacteria actively remodel tumors. Specifically, intravenous injection of F. nucleatum led to comparable microniche formation with extracellular bacteria and disrupted epithelial cell-to-cell interactions, mirroring the patient tissue observations.

To investigate clinical relevance, the authors analyzed tumor samples from a cohort of 52 treatment-naïve CRC patients. They found that regions with high bacterial burden often correlated with reduced proliferation markers and cancer cell density, suggesting that bacterial microniches are common in human tumors. Additionally, they assessed sequencing data from biopsies of 92 CRC patients to determine Fusobacterium and other bacteria load. Non-responders to neoadjuvant therapy had a higher intratumoral Fusobacterium burden than responders.

Importantly, they found that while F. nucleatum suppresses proliferation programs, it simultaneously activates inflammatory and pro-metastatic pathways, creating a tumor state that is less sensitive to chemotherapy yet more aggressive and immune-evasive. Together, these findings highlight how tumor architecture and bacterial colonization cooperate to reprogram cancer cells toward treatment resistance and relapse, pointing to microbial modulation as a promising frontier in cancer treatment.

Dr. Galeano Niño is building upon this work in his independent lab at the University of Texas at El Paso: “Future research should aim to elucidate the molecular mechanisms underlying these bacteria-cancer interactions. Our lab uses biophysical methods to measure intercellular adhesion forces at single-cell resolution. The mechanical properties of these bacterial-cancer interactions may determine the molecular programs driving cancer cell quiescence. We believe the transition of hyperproliferative states toward quiescence is fundamental for cancer cells to adapt to necrotic regions within the tumor tissue. In more favorable conditions, dormant cancer cells reawaken, forming tumors in the form of relapse and recurrence after cancer therapy.”

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members (former) Drs. Chris Johnston and Susan Bullman contributed to this work.

The spotlighted research was funded by the Experimental Histopathology, Comparative Medicine, Cellular Imaging Shared Resource (CISR), and Genomics & Bioinformatics Shared Resources of the Fred Hutch, the Fred Hutch Interdisciplinary Training Grant in Cancer Research, the Institutional Tissue Bank and Core Facilities Histology Laboratory at MD Anderson Cancer Center, the Imaging & Behavioral Neuroscience (IBN) Facility Imaging Core at The University of Texas at El Paso, the National Institutes of Health, the CPRIT Scholar in Cancer Research award, James P. Allison Institute funds, Fred Hutch startup funds, the W.M. Keck Research Foundation, the CRI Irvington Postdoctoral Fellowship, UTEP start-up funds, CPRIT, and TREC grant.

Galeano Niño JL, Ponath F, Ajisafe VA, Becker CR, Kempchinsky AG, Zepeda-Rivera MA, Gomez JA, Wu H, Terrazas JG, Bouzek H et al. 2026. Tumor-infiltrating bacteria disrupt cancer epithelial cell interactions and induce cell-cycle arrest. Cancer Cell. https://doi.org/10.1016/j.ccell.2025.09.010