Bacteria Living Inside Tumors Drive Cancer Spread and Open New Treatment Doors

The discovery that bacteria reside not just in the tumor microenvironment but physically inside cancer cells has fundamentally shifted our understanding of cancer biology. This comprehensive review, published in Military Medical Research, synthesizes findings from large-scale sequencing studies, mechanistic research, and emerging therapeutic strategies to map what is known — and what remains unknown — about intratumoral microbiota, with particular focus on intracellular bacteria and their roles in cancer progression and treatment.

The landmark study by Nejman et al. analyzed 1,010 tumor samples and 516 healthy tissue samples across seven cancer types — breast, lung, ovarian, pancreatic, melanoma, bone, and brain — and found bacterial enrichment in all tumor types compared to controls. Critically, bacteria were detected even in anatomically isolated tumors such as glioblastoma and ovarian cancer, ruling out simple surface contamination. Using 16S rRNA sequencing, the study demonstrated that intratumoral microbial compositions are cancer-type specific, with significant differences in beta diversity and distinct microbiome profiles at both order and species levels. Specific metabolic capabilities — such as hydroxyproline degradation in bone tumors and processing of cigarette smoke chemicals in lung cancer — may explain why certain bacterial taxa preferentially colonize specific cancer types.

The review details three proposed routes by which bacteria enter cancer cells: direct invasion via endocytosis and macropinocytosis, exploitation of cytoskeletal dynamics (including actin polymerization and microtubule networks), and co-option of autophagy pathways that normally clear intracellular pathogens. Once inside, bacteria deploy multiple survival strategies including forming biofilms, manipulating lysosomal degradation, and suppressing reactive oxygen species production. Notably, intracellular bacteria have been shown to significantly enhance metastatic potential — bacteria residing in cancer cells can protect them during circulation in the bloodstream by promoting cytoskeletal remodeling that facilitates extravasation at distant sites.

The immunomodulatory effects of intratumoral bacteria are complex and bidirectional. These microbes can activate pattern recognition receptors (TLRs, NLRs) on immune cells, triggering inflammatory cascades that paradoxically both recruit anti-tumor immune cells and create immunosuppressive niches. Bacteria-derived metabolites, including short-chain fatty acids and lipopolysaccharides, modulate T-cell differentiation, macrophage polarization, and dendritic cell function within the tumor immune microenvironment. Epigenetic reprogramming via bacterial metabolites — altering DNA methylation and histone modification patterns in cancer cells — represents another mechanism through which intratumoral microbes influence tumor evolution and therapy resistance.

Perhaps the most clinically exciting section of the review covers therapeutic exploitation of intratumoral bacteria. Engineered bacterial strains — particularly attenuated Salmonella, Listeria, and Clostridium species — are being developed as tumor-targeted drug delivery vehicles, capable of preferentially colonizing hypoxic tumor cores inaccessible to conventional therapies. Synthetic biology approaches allow bacteria to be programmed to produce anti-tumor payloads, cytokines, or checkpoint inhibitor modulators in situ. Early-phase clinical trials using bacterial vectors have shown proof-of-concept for tumor colonization and payload delivery. The review also highlights that antibiotic co-treatment strategies can sensitize tumors to chemotherapy by eliminating bacteria that metabolically inactivate drugs like gemcitabine — a finding with immediate clinical implications for pancreatic cancer treatment.