The human microbiome, composed of microorganisms such as bacteria, fungi, and viruses, plays a crucial role in our health. However, in recent years, research has revealed that not only the gut microbiome is relevant, but also the microbiome present within tumors: the intratumoral microbiome. This discovery is transforming our understanding of how cancer interacts with the body and how it could be treated.
Contrary to previous beliefs, tumor tissues are not sterile. Each type of tumor harbors a unique bacterial signature, which can influence cancer progression and treatment efficacy both positively and negatively. Recent studies have shown that bacteria within tumors can perform various functions, such as inducing DNA damage, promoting epithelial-mesenchymal transition (a key process in metastasis), and modulating the immune system toward a protumoral or antitumoral profile, depending on the balance between beneficial bacterial species (symbionts) and harmful ones (pathobionts).
Key Interactions Between the Microbiome and Cancer
- Promotion of Metastasis: Intratumoral bacteria can influence metastasis formation by altering the permeability of vascular barriers, as in the case of colorectal cancer, where bacteria facilitate dissemination to the liver. Additionally, some bacteria protect tumor cells from mechanical stress during migration through the bloodstream, improving their survival.
- Drug Resistance: Certain bacteria, such as Fusobacterium nucleatum, can degrade chemotherapeutic drugs like gemcitabine and 5-fluorouracil, reducing their efficacy. However, combining chemotherapy with targeted antibiotics has been shown to restore treatment sensitivity, opening new therapeutic opportunities.
- Induction of DNA Damage: Some bacteria produce metabolites or enzymes that generate reactive oxygen species (ROS) or disrupt DNA repair mechanisms in tumor cells. This cumulative DNA damage can accelerate mutations and promote tumor progression, highlighting the dual nature of the microbiome in the tumor microenvironment.
- Immune System Modulation: While certain bacteria create an immunosuppressive environment by attracting cells such as M2 macrophages and regulatory T cells, others promote increased infiltration of cytotoxic T cells and polarize macrophages toward an antitumoral profile (M1). Additionally, the interaction between bacterial metabolites and tumor signaling pathways can directly alter cancer progression.
Figure 1. the role of the intratumoral microbiome in cancer, highlighting its influence on tumor dissemination, progression, drug resistance, and immune evasion. Bacteria within tumors can enhance metastasis, induce DNA damage, degrade chemotherapeutic drugs, and manipulate the immune system, either suppressing or activating its response. This dynamic ecosystem underscores the dual nature of the microbiome in cancer, acting as both a challenge and an opportunity for developing targeted therapies.
The intratumoral microbiome offers new opportunities for developing innovative treatments. Some promising approaches include:
- Bacterial Peptide-Based Vaccines: Tumors harboring bacteria can present bacterial peptides to T cells, triggering targeted immune responses. This could become a universal strategy to treat hard-to-reach tumors.
- Genetically Modified Bacteria: Strains such as Lactococcus lactis, engineered to release immunomodulatory factors, have shown reduced tumor growth in animal models by activating local and systemic immune responses.
- Microbiome Modulation: Increasing intratumoral bacterial diversity is correlated with longer patient survival. Additionally, administering bacterial metabolites (postbiotics) could enhance the efficacy of traditional treatments like immunotherapy. Fecal microbiota transplants are also being explored to alter the tumor environment and boost therapy responses.
- Combination Therapies: Integrating microbiome-based strategies with immunotherapies or chemotherapies could overcome treatment resistance and improve clinical outcomes.
We are at a paradigm-shifting moment in cancer research. Just as immunotherapy revolutionized the field over the last decade, understanding the intratumoral microbiome could drive the next major breakthrough. Identifying how bacteria interact with the tumor microenvironment will not only enable the development of more effective treatments but also allow for personalized therapies tailored to each patient’s unique needs. Additionally, this emerging field underscores the importance of a multidisciplinary approach combining molecular biology, microbiology, and clinical oncology.
Main Reference:
Ferrari, V., & Rescigno, M. (2023). The intratumoral microbiota: friend or foe? Trends in Cancer, 9(6), 472–479. https://doi.org/10.1016/j.trecan.2023.03.005
Other References:
Sender, R., Fuchs, S., & Milo, R. (2016). Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS biology, 14(8), e1002533. https://doi.org/10.1371/journal.pbio.1002533
Human Microbiome Project Consortium (2012). A framework for human microbiome research. Nature, 486(7402), 215–221. https://doi.org/10.1038/nature11209
Gill, S. R., Pop, M., Deboy, R. T., Eckburg, P. B., Turnbaugh, P. J., Samuel, B. S., Gordon, J. I., Relman, D. A., Fraser-Liggett, C. M., & Nelson, K. E. (2006). Metagenomic analysis of the human distal gut microbiome. Science (New York, N.Y.), 312(5778), 1355–1359. https://doi.org/10.1126/science.1124234
