Overview

The intratumoral microbiota refers to the diverse and dynamic community of microorganisms, including bacteria, fungi, viruses, mycoplasmas, and other microbial species, that reside within the tumor tissues.^[1] These microbial populations form an integral component of the tumor microenvironment (TME), a specialized niche surrounding the tumor cells. The intratumoral microbiota is not a passive bystander; it interacts intricately with tumor cells, stromal cells, immune cells, and the extracellular matrix, influencing various biological processes. These microorganisms can directly and indirectly affect tumor growth, metastasis, immune evasion, angiogenesis, and inflammation. For instance, some bacteria produce genotoxic metabolites, which lead to DNA damage and promote mutations that drive carcinogenesis.^[2] Others modulate the immune system, either by stimulating immune responses that suppress tumors or, conversely, by fostering an immunosuppressive microenvironment that allows tumor progression.^[3] The microbiota can alter the tumor’s metabolic landscape, influencing nutrient availability, oxygen levels, and pH, which can, in turn, affect cancer cell survival and proliferation.^[4] The composition of the intratumoral microbiota can vary significantly between different types of cancer and even within different regions of the same tumor, contributing to tumor heterogeneity.

Origin of Intratumoural Microbiota

The intratumoral microbiota originates from multiple sources, each playing a unique role in shaping the tumor microenvironment and influencing cancer progression.

Origin	Description
Resident Microbiota	The resident microbiota referes to the microorganisms native to the tissue where the tumor originates.[5] Every tissue in the human body has a unique microbial community shaped by environmental factors, genetic predispositions, and immune responses. In some cases, the microbes native to these tissues may play a significant role in the initiation and progression of cancer.
Hematogenous Spread	Hematogenous spread involves the migration of microbes through the bloodstream, potentially accompanying metastatic cancer cells.[6] As cancer cells disseminate from their original tumor site to distant organs, microbes from the primary tumor or surrounding tissues may also travel with them, colonizing new tumor sites.
Retrograde Flow	This migration is particularly significant in cancers affecting the liver, pancreas, and biliary tract, where microbes from the gastrointestinal tract may travel via the bile ducts, influencing the tumor microenvironment.[7]
Oral-Derived Microbiota	The oral cavity is a significant entry point for microorganisms, and these microbes can migrate from the mouth to distant tumor sites, contributing to cancer progression.[8] Oral-derived microbiota have been implicated in cancers of the head and neck, lung, and gastrointestinal regions.[9]

Composition and Heterogeneity

The composition of the intratumoral microbiota is highly heterogeneous, varying not only between tumor types but also within different regions of the same tumor. This diversity suggests that microbial communities adapt to the unique environmental conditions present in specific tumor microenvironments.

Microbial Diversity

The intratumoral microbiota is predominantly composed of bacterial species, although fungi, viruses, and other microorganisms are also present in lower abundances.^[10] Bacterial dominance is a consistent feature across multiple cancer types, but the specific composition varies depending on the tumor site, stage, and microenvironmental conditions. For instance, Fusobacterium nucleatum is highly prevalent in colorectal cancer, whereas Streptococcus species are more associated with breast tumors.^[11][12] Fungal populations, such as Candida species, and viruses, including human papillomavirus (HPV), are typically present at lower relative abundances; yet, they can exert significant effects on tumor biology through immune modulation and inflammation.^[13] This diversity reflects the complex interactions between microbes and tumor cells: bacteria can produce metabolites that modulate tumor growth and immune evasion, viruses can integrate into host genomes, causing mutations or oncogene activation, and fungi can trigger localized inflammation or influence immune cell recruitment.^[14][15] Consequently, microbial diversity is not merely a reflection of colonization but is closely linked to tumor progression, therapy response, and patient outcomes.

Spatial and Temporal Variability

The composition of intratumoral microbiota exhibits substantial spatial and temporal heterogeneity, reflecting both tumor type specificity and intra-tumor variability.^[16] Different cancer types harbor distinct microbial profiles, suggesting that tumor tissue characteristics, such as vascularization, metabolic activity, and immune landscape, select for particular microbial communities.^[17] For example, pancreatic tumors often show enrichment of gut-derived bacteria due to retrograde ductal migration, whereas lung tumors may contain microbes originating from the oral cavity.^[18] Within a single tumor, microbial populations can vary between regions, with hypoxic or necrotic zones harboring different communities than perivascular areas. ^[19]Temporally, the microbiota may shift as tumors progress, metastasize, or respond to therapy, influenced by changes in nutrient availability, immune pressure, or treatment interventions. This spatial and temporal heterogeneity is critical for understanding tumor biology, as localized microbial populations can modulate microenvironmental conditions, affect therapy efficacy, and contribute to tumor heterogeneity and adaptation.^[20] Recognizing these patterns provides insights into personalized therapeutic approaches targeting both tumor cells and associated microbial communities.

Mechanisms of Tumorigenesis

Intratumoral microbiota can contribute to tumorigenesis through both direct and indirect mechanisms. Directly, certain microbes produce genotoxic metabolites that induce DNA damage, mutations, and chromosomal instability, directly promoting malignant transformation.^[21] Microbial presence can trigger inflammatory pathways by modulating cytokine release, creating a chronic inflammatory microenvironment that fosters tumor initiation, progression, and angiogenesis.^[22] Indirectly, microbes influence tumor development by modulating immune responses, affecting the behavior of immune cells such as T cells, macrophages, and dendritic cells, which can lead to immune evasion and enhanced metastasis.^[23] Microbial metabolites also induce metabolic alterations in tumor cells, supporting their survival, proliferation, and adaptation within the nutrient-limited and hypoxic tumor microenvironment.^[24][25] Collectively, these mechanisms highlight the multifaceted role of intratumoral microbiota in shaping tumor biology and influencing cancer progression, underscoring their potential as therapeutic targets

Impact on Cancer Therapy

The intratumoral microbiota has emerged as a crucial factor influencing cancer treatment outcomes. Its presence within the tumor microenvironment can modulate responses to therapies, either enhancing their effectiveness or contributing to resistance. This dual role makes the microbiota an important consideration in designing more effective, personalized treatment strategies.

Therapeutic Implications

Microbial communities within tumors can significantly impact immunotherapy and chemotherapy. In the context of immunotherapy, the intratumoral microbiota can either bolster or dampen treatment efficacy.^[26] Certain bacteria stimulate antigen-presenting cells and activate cytotoxic T cells, enhancing responses to checkpoint inhibitors or adoptive cell therapies. Conversely, other microbial populations can create an immunosuppressive environment, reducing the effectiveness of these treatments.^[27] Similarly, the microbiota can affect chemotherapy outcomes. Some intratumoral microbes metabolize chemotherapeutic drugs, lowering their cytotoxic potential, while others trigger tumor cell stress responses that promote drug resistance.^[28][29] These interactions underline the complexity of tumor-microbe dynamics and highlight the microbiota’s role as more than a passive inhabitant.

Potential Therapeutic Strategies

Strategy	Description	Mechanism & Mode of Action
Microbiota Modulation	Altering the tumor-associated microbial composition through targeted interventions	Use of narrow-spectrum antibiotics, bacteriophages, or engineered microbial consortia to selectively reduce immunosuppressive or chemotherapy-metabolizing microbes.[30] It can also involve gene editing of microbial populations to enhance anti-tumor effects.
Probiotic Interventions	Introduction of beneficial microorganisms directly into the patient	Administering live bacterial strains known to promote immune activation that can colonize tumor-adjacent tissues and influence immune cell infiltration.[31][32]
Fecal Microbiota Transplant (FMT)	Transfer of whole microbial communities from healthy donors to patients	Introduces a diverse, balanced microbiota to reprogram the tumor microenvironment, restore immune homeostasis, and outcompete harmful microbial populations.[33]
Microbial Metabolite Supplementation	Administration of specific microbial-derived metabolites with therapeutic properties	Providing compounds such as short-chain fatty acids, secondary bile acids, or bacteriocins known to modulate immune responses, reduce inflammation, or induce tumor cell apoptosis.[34][35]

Clinical Relevance and Future Directions

The study of the intratumoral microbiota holds great promise for improving both cancer diagnosis and treatment. One of the most exciting possibilities lies in its diagnostic potential; identifying specific microbial signatures within tumors could lead to new biomarkers for early detection and prognosis, allowing for more personalized and timely interventions. In terms of treatment, the concept of microbiota-targeted therapies is gaining traction. By modifying the microbial community within the tumor, we could potentially inhibit tumor growth, reduce metastasis, and improve the efficacy of conventional therapies such as chemotherapy and immunotherapy. For instance, bacteria-induced thrombosis in tumor blood vessels not only targets cancer cells directly but also provides a novel method to induce tumor necrosis, circumventing the need for conventional systemic chemotherapy.^[36]

The potential to manipulate the microbiota for therapeutic benefit is becoming an exciting frontier in cancer treatment. However, these advancements are not without their challenges. Understanding the complex interactions between microbes, tumor cells, and the immune system is important, as these relationships are often intricate and vary across individuals. As our understanding of the microbiota continues to grow, overcoming these hurdles could open up transformative new approaches to cancer treatment, making it possible to tailor therapies to individual patients based on their unique microbial profiles.

Research Feed

References

1. Intratumoral microbiota: Implications for cancer onset, progression, and therapy.. Wu, J., Zhang, P., Mei, W., & Zeng, C. (2024).. (Frontiers in Immunology, 14, 1301506.)
2. Intratumoural microbiota: a new frontier in cancer development and therapy.. Cao, Y., Xia, H., Tan, X. et al.. (Sig Transduct Target Ther 9, 15 (2024).)
3. The intratumoral microbiota: A new horizon in cancer immunology.. Liu, W., Li, Y., Wu, P., Guo, X., & Xu, Y. (2024).. (Frontiers in Cellular and Infection Microbiology, 14, 1409464.)
4. Intratumoural microbiota: a new frontier in cancer development and therapy.. Cao, Y., Xia, H., Tan, X. et al.. (Sig Transduct Target Ther 9, 15 (2024).)
5. Intratumoral microbiota: Implications for cancer onset, progression, and therapy.. Wu, J., Zhang, P., Mei, W., & Zeng, C. (2024).. (Frontiers in Immunology, 14, 1301506.)
6. Intratumoral microbiota: Roles in cancer initiation, development and therapeutic efficacy.. Yang, L., Li, A., Wang, Y., & Zhang, Y. (2023).. (Signal Transduction and Targeted Therapy, 8(1), 1-24.)
7. The intratumoral microbiota: A new horizon in cancer immunology.. Liu, W., Li, Y., Wu, P., Guo, X., & Xu, Y. (2024).. (Frontiers in Cellular and Infection Microbiology, 14, 1409464.)
8. Oral Microbiota and Tumor—A New Perspective of Tumor Pathogenesis.. Li, S., He, M., Lei, Y., Liu, Y., Li, X., Xiang, X., Wu, Q., & Wang, Q. (2022).. (Microorganisms, 10(11), 2206.)
9. Intratumoural microbiota: a new frontier in cancer development and therapy.. Cao, Y., Xia, H., Tan, X. et al.. (Sig Transduct Target Ther 9, 15 (2024).)
10. The intratumoral microbiota: A new horizon in cancer immunology.. Liu, W., Li, Y., Wu, P., Guo, X., & Xu, Y. (2024).. (Frontiers in Cellular and Infection Microbiology, 14, 1409464.)
11. Intratumoural microbiota: a new frontier in cancer development and therapy.. Cao, Y., Xia, H., Tan, X. et al.. (Sig Transduct Target Ther 9, 15 (2024).)
12. Intratumor microbiota and colorectal cancer: Comprehensive and lucid review.. Zong, Z., Zeng, W., Li, Y., Wang, M., Cao, Y., Cheng, X., Jin, Z., Mao, S., & Zhu, X. (2024).. (Chinese Journal of Cancer Research, 36(6), 683.)
13. Role of Fungi in Tumorigenesis: Promises and Challenges.. Guglietta, S., Li, X., & Saxena, D. (2024).. (Annual Review of Pathology, 20(1), 459.)
14. Intratumoral Microbiota: Insights from Anatomical, Molecular, and Clinical Perspectives.. Lombardo, C., Fazio, R., Sinagra, M., Gattuso, G., Longo, F., Lombardo, C., Salmeri, M., Zanghì, G. N., & Erika Loreto, C. A. (2024).. (Journal of Personalized Medicine, 14(11), 1083.)
15. Role of Fungi in Tumorigenesis: Promises and Challenges.. Guglietta, S., Li, X., & Saxena, D. (2024).. (Annual Review of Pathology, 20(1), 459.)
16. Unveiling the intratumoral microbiota within cancer landscapes.. Che, S., Yan, Z., Feng, Y., & Zhao, H. (2024).. (IScience, 27(6), 109893.)
17. Spatial Heterogeneity of Intratumoral Microbiota: A New Frontier in Cancer Immunotherapy Resistance.. Tan, Q., Cao, X., Zou, F., Wang, H., Xiong, L., & Deng, S. (2025).. (Biomedicines, 13(5), 1261.)
18. The microbial landscape of tumors: A deep dive into intratumoral microbiota.. Asgharzadeh, S., Pourhajibagher, M., & Bahador, A. (2025).. (Frontiers in Microbiology, 16, 1542142.)
19. Spatial Heterogeneity of Intratumoral Microbiota: A New Frontier in Cancer Immunotherapy Resistance.. Tan, Q., Cao, X., Zou, F., Wang, H., Xiong, L., & Deng, S. (2025).. (Biomedicines, 13(5), 1261.)
20. Spatial Heterogeneity of Intratumoral Microbiota: A New Frontier in Cancer Immunotherapy Resistance.. Tan, Q., Cao, X., Zou, F., Wang, H., Xiong, L., & Deng, S. (2025).. (Biomedicines, 13(5), 1261.)
21. Intratumoral microbiota: Roles in cancer initiation, development and therapeutic efficacy.. Yang, L., Li, A., Wang, Y., & Zhang, Y. (2023).. (Signal Transduction and Targeted Therapy, 8(1), 1-24.)
22. The Role of Inflammation in Cancer: Mechanisms of Tumor Initiation, Progression, and Metastasis.. Nishida, A., & Andoh, A. (2024).. (Cells, 14(7), 488.)
23. Intratumoral microbiota: Roles in cancer initiation, development and therapeutic efficacy.. Yang, L., Li, A., Wang, Y., & Zhang, Y. (2023).. (Signal Transduction and Targeted Therapy, 8(1), 1-24.)
24. Metabolites and the tumor microenvironment: From cellular mechanisms to systemic metabolism.. Elia, I., & Haigis, M. C. (2021).. (Nature Metabolism, 3(1), 21.)
25. De-coding the complex role of microbial metabolites in cancer.. Pérez Escriva, P., Correia Tavares Bernardino, C., & Letellier, E. (2025).. (Cell Reports, 44(3), 115358.)
26. The role of the microscopic world: Exploring the role and potential of intratumoral microbiota in cancer immunotherapy.. Zhang, L., & Yu, L. (2024).. (Medicine, 103(20), e38078.)
27. Bacteria-based immunotherapy for cancer: A systematic review of preclinical studies.. Zhou, M., Tang, Y., Xu, W., Hao, X., Li, Y., Huang, S., Xiang, D., & Wu, J. (2023).. (Frontiers in Immunology, 14, 1140463.)
28. Intratumoral microbiome: Implications for immune modulation and innovative therapeutic strategies in cancer.. Wang, N., Wu, S., Huang, L., Hu, Y., He, X., He, J., Hu, B., Xu, Y., Rong, Y., Yuan, C., Zeng, X., & Wang, F. (2025).. (Journal of Biomedical Science, 32, 23.)
29. The role of gut microbiota and metabolites in cancer chemotherapy.. Li, S., Zhu, S., & Yu, J. (2023).. (Journal of Advanced Research, 64, 223.)
30. Cancer pharmacomicrobiomics: Targeting microbiota to optimise cancer therapy outcomes.. Lung-Ngai Ting, N., Cheuk-Hay Lau, H., & Yu, J. (2022).. (Gut, 71(7), 1412.)
31. Probiotics Mechanism of Action on Immune Cells and Beneficial Effects on Human Health.. Mazziotta, C., Tognon, M., Martini, F., Torreggiani, E., & Rotondo, J. C. (2023).. (Cells, 12(1), 184.)
32. Role of Probiotics against Human Cancers, Inflammatory Diseases, and Other Complex Malignancies.. Naeem, H., Hassan, H. U., Shahbaz, M., Imran, M., Memon, A. G., Hasnain, A., Murtaza, S., Alsagaby, S. A., Abdulmonem, W. A., Hussain, M., Abdelgawad, M. A., Ghoneim, M. M., & Jbawi, E. A. (2023).. (Journal of Food Biochemistry, 2024(1), 6632209.)
33. Fecal microbiota transplantation and next-generation therapies: A review on targeting dysbiosis in metabolic disorders and beyond.. Sahle, Z., Engidaye, G., Gebreyes, D. S., Adenew, B., & Abebe, T. A. (2024).. (SAGE Open Medicine, 12, 20503121241257486.)
34. The role of key gut microbial metabolites in the development and treatment of cancer.. Jaye, K., Li, C. G., Chang, D., & Bhuyan, D. J. (2022).. (Gut Microbes, 14(1), 2038865.)
35. The Effect of Microbiome-Derived Metabolites in Inflammation-Related Cancer Prevention and Treatment.. Mafe, A. N., & Büsselberg, D. (2025).. (Biomolecules, 15(5), 688.)
36. Tumour-resident oncolytic bacteria trigger potent anticancer effects through selective intratumoural thrombosis and necrosis.. Iwata, S., Nishiyama, T., Sakari, M., Doi, Y., Takaya, N., Ogitani, Y., Nagano, H., Fukuchi, K., & Miyako, E. (2025).. (Nature Biomedical Engineering, 1-16.)