Tumor-infiltrating Bacteria Induce Quiescence and Therapy Resistance

Tumor-infiltrating bacteria are emerging as key modulators of the tumor microenvironment, particularly in mucosal cancers. In colorectal cancer (CRC), enrichment of Fusobacterium nucleatum has been linked to tumor progression and therapy resistance, yet its impact on tumor architecture remains unclear. Galeano Niño and colleagues used multiplex immunohistochemistry to map human CRC and oral squamous cell carcinoma samples, identifying bacteria-rich microniches in necrotic regions where cancer epithelial cells were dispersed and less proliferative. Across samples from patients with CRC, bacterial microniches were detected in half of tumors and correlated with lower cancer cell density and proliferation. In 2D and 3D models of CRC, F. nucleatum localized to intercellular junctions, preventing spheroid formation and inducing G0–G1 arrest. Similar effects were observed with other Fusobacterium species and Bacteroides fragilis, suggesting that G0–G1 arrest is a conserved epithelial response to select bacteria. In mouse CRC spheroids, this quiescence was reversible, delaying tumor formation while enabling cancer cells to recover after 5-fluorouracil (5-FU) treatment. Consistently, tumors pre-exposed to F. nucleatum and 5-FU regrew faster post-therapy, and rectal cancer biopsies with higher bacterial loads exhibited poorer responses to neoadjuvant therapy, indicating that bacterial-induced quiescence protects cancer cells during chemotherapy. Mechanistically, bacterial exposure disrupted epithelial–epithelial contacts, leading to more G0–G1 arrested cells in 3D cultures, where intercellular junctions are essential. Transcriptomic profiling of 3D versus 2D cultures exposed to F. nucleatum showed reduced transcription, translation, and cell-cycle pathways in 3D-grown cells, with both systems upregulating inflammatory and metastatic programs. Spatial single-cell transcriptomic analysis of human CRC tumors revealed bacteria-rich microniches enriched for immune cells, while cancer epithelial cells within these niches exhibited reduced transcription and antigen presentation. Together, these findings identify extracellular Fusobacterium as inducers of reversible G0–G1 quiescence in cancer epithelial cells and highlight tumor-infiltrating bacteria as therapeutic targets to resensitize dormant cancer cells.Galeano Niño JL, Ponath F, Ajisafe VA, Becker CR, Kempchinsky AG, Zepeda-Rivera MA, et al. Tumor-infiltrating bacteria disrupt cancer epithelial cell interactions and induce cell-cycle arrest. Cancer Cell 2025 Oct 16 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.