The Microbial Conductor: Orchestrating Cancer Hallmarks through the Intratumoral Microbiome
Microbiome and cancer hallmarks
DOI:
https://doi.org/10.29409/s5c44z69Keywords:
Cancer hallmarks , Intratumoral microbiome , Immune modulation , Microbiota–cancer interaction , Tumor microenvironmentAbstract
The intratumoral microbiota, which consists of a variety of bacteria, fungi, and viruses living inside the tumor, is gaining recognition as a multifunctional factor that influences cancer development in multiple ways, similar to a “microbiological conductor.” The structure of the intratumoral microbiota is highly heterogeneous among different individuals and correlates closely with the immune response of the host, the tumor microenvironment (TME), and therapy effectiveness. Certain types of microbes can act as a conductor for tumor growth and progression through carcinogen production, inflammation disruption, or immune escape.
In addition, the intratumor microbiome may affect the response to therapy by affecting the metabolism of drugs used during chemotherapy, as well as the effectivity of immuno-oncology drugs. The study of the intratumoral microbiome and its interaction with tumors thus has huge possibilities that may help us understand the basic mechanisms responsible for tumor formation and growth and at the same time provide new opportunities for personalized therapies in oncology. This review discusses the biological functions of the microbial community in regulating hallmarks of cancer, the current state of knowledge about its multidimensional interactions that lead to tumor growth, and the potential of microbiome-based approaches, considering recent developments. Further scientific efforts will be required to overcome methodological challenges, which include multi-omics studies combined with functional validation.
Author Declarations:
Authors’ Contributions
All authors contributed equally to the conception and design of the review. All authors participated in the literature search, data interpretation, manuscript preparation, critical revision of the manuscript, and approval of the final version for pub-lication. All authors read and approved the final manuscript.
Acknowledgments
The authors would like to acknowledge all researchers whose published studies contributed to the preparation of this review.
Ethical Approval and Consent to Participate
Not applicable. This study is a narrative review article based exclusively on previously published literature and did not in-volve human participants, animals, clinical specimens, or patient data. Therefore, ethical approval and informed consent were not required.
Consent for Publication
Not applicable.
Availability of Data and Materials
No new datasets were generated or analyzed during this study. All information discussed in this review was obtained from previously published articles cited in the reference list.
Funding
This research received no external funding. The study was self-funded by the authors.
Competing Interests
The authors declare that they have no competing interests or conflicts of interest regarding the publication of this manuscript.
References
1- Gao, F., Yu, B., Rao, B., Sun, Y., Yu, J., Wang, D., et al. (2022). The effect of the intratumoral microbiome on tumor occurrence, progression, prognosis and treatment. Front. Immunol. 13:1051987. doi: 10.3389/fimmu.2022.1051987. DOI: https://doi.org/10.3389/fimmu.2022.1051987
2- Qu, D., Wang, Y., Xia, Q., Chang, J., Jiang, X., and Zhang, H. (2022). Intratumoral microbiome of human primary liver cancer. Hepatol. Commun. 6, 1741–1752. doi: 10.1002/hep4.1908. DOI: https://doi.org/10.1002/hep4.1908
3- Riquelme, E., Zhang, Y., Zhang, L., Montiel, M., Zoltan, M., Dong, W., et al. (2019). Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell 178, 795–806.e12. doi: 10.1016/j.cell.2019.07.008 DOI: https://doi.org/10.1016/j.cell.2019.07.008
4- Sheehan, D. H., Asam, K., Knight, N. D., Patel, J. J., Stewart, J. A., Molina, P. A., et al. (2025). Altered bacteria abundance is associated with outcomes in head and neck squamous cell carcinoma. Otolaryngol. Neck Surg. 173, 420–432. doi:10.1002/ohn.1262. DOI: https://doi.org/10.1002/ohn.1262
5- Nejman, D., Livyatan, I., Fuks, G., Gavert, N., Zwang, Y., Geller, L. T., et al. (2020). The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368, 973–980. doi: 10.1126/science.aay9189. DOI: https://doi.org/10.1080/2162402X.2020.1800957
6- Ochi, T., Fujiki, R., Fukuyo, M., Rahmutulla, B., Nakagawa, T., Ota, M., et al. (2025). Association of intratumoral bacterial abundance with lung cancer prognosis in the Chiba University Hospital cohort. Cancer Sci. 116, 2040–2046. doi:10.1111/cas.70080. DOI: https://doi.org/10.1111/cas.70080
7- Mou, W., Deng, Z., Zhu, L., Jiang, A., Lin, A., Xu, L., et al. (2025). Intratumoral mycobiome heterogeneity influences the tumor microenvironment and immunotherapy outcomes in renal cell carcinoma. Sci. Adv. 11:eadu1727. doi:10.1126/sciadv.adu1727.
8- Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science. 2021 Mar 26;371(6536):eabc4552. doi:10.1126/science.abc4552. DOI: https://doi.org/10.1126/science.abc4552
9- Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy. Science. 2018;359(6371):91–97. doi:10.1126/science.aan3706. DOI: https://doi.org/10.1126/science.aan3706
10- Hanahan, D. (2022). Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46. doi: 10.1158/2159-8290.CD-21-1059 DOI: https://doi.org/10.1158/2159-8290.CD-21-1059
11- Hanahan, D., and Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674. doi: 10.1016/j.cell.2011.02.013. DOI: https://doi.org/10.1016/j.cell.2011.02.013
12- Hanahan, D., and Weinberg, R. A. (2000). The hallmarks of cancer. Cell 100, 57–70. doi: 10.1016/S0092-8674(00)81683-9. DOI: https://doi.org/10.1016/S0092-8674(00)81683-9
13- Tsay, J. J., Wu, B. G., Badri, M. H., Clemente, J. C., Shen, N., Meyn, P., et al. (2018). Airway microbiota is associated with upregulation of the PI3K pathway in lung cancer. Am. J. Respir. Crit. CareMed. 198, 1188–1198. doi: 10.1164/rccm.201710-2118OC. DOI: https://doi.org/10.1164/rccm.201710-2118OC
14- Fruman, D. A., Chiu, H., Hopkins, B. D., Bagrodia, S., Cantley, L. C., and Abraham, R. T. (2017). The PI3K pathway in human disease. Cell 170, 605–635. doi: 10.1016/j.cell.2017.07.029. DOI: https://doi.org/10.1016/j.cell.2017.07.029
15- Mann, E. R., Lam, Y. K., and Uhlig, H. H. (2024). Short-chain fatty acids: linking diet, the microbiome and immunity. Nat. Rev. Immunol. 24, 577–595. doi: 10.1038/s41577-024-01014-8. DOI: https://doi.org/10.1038/s41577-024-01014-8
16- Fulbright, L. E., Ellermann, M., and Arthur, J. C. (2017). The microbiome and the hallmarks of cancer. PLoS Pathog. 13:e1006480. doi: 10.1371/journal.ppat.1006480. DOI: https://doi.org/10.1371/journal.ppat.1006480
17- He, Y., Fu, L., Li, Y., Wang, W., Gong, M., Zhang, J., et al. (2021). Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. Cell. Metab. 33, 988–1000.e7. doi: 10.1016/j.cmet.2021.03.002. DOI: https://doi.org/10.1016/j.cmet.2021.03.002
18- Buti, L., Spooner, E., Van der Veen, A. G., Rappuoli, R., Covacci, A., and Ploegh, H. L. (2011). Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host. Proc. Natl. Acad. Sci. U. S. A. 108, 9238–9243. doi: 10.1073/pnas.1106200108. DOI: https://doi.org/10.1073/pnas.1106200108
19- Lu, R., Wu, S., Zhang, Y. G., Xia, Y., Liu, X., Zheng, Y., et al. (2014). Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway. Oncogenesis 3:e105. doi: 10.1038/oncsis.2014.20. DOI: https://doi.org/10.1038/oncsis.2014.20
20- Fridman, J. S., and Lowe, S. W. (2003). Control of apoptosis by p53. Oncogene 22, 9030–9040. doi: 10.1038/sj.onc.1207116. DOI: https://doi.org/10.1038/sj.onc.1207116
21- Kastenhuber, E., and Lowe, S. (2017). Putting p53 in context. Cell 170, 1062–1078. doi: 10.1016/j.cell.2017.08.028. DOI: https://doi.org/10.1016/j.cell.2017.08.028
22- Bieging-Rolett, K. T., Kaiser, A. M., Morgens, D. W., Boutelle, A. M., Seoane, J. A., Van Nostrand, E. L., et al. (2020). Zmat3 is a key splicing regulator in the p53 tumor suppression program. Mol. Cell. 80, 452–469.e9. doi: 10.1016/j.molcel.2020.10.022. DOI: https://doi.org/10.1016/j.molcel.2020.10.022
23- Aschtgen, M. S., Fragkoulis, K., Sanz, G., Normark, S., Selivanova, G., Henriques-Normark, B., et al. (2022). Enterobacteria impair host p53 tumor suppressor activity through mRNA destabilization. Oncogene 41, 2173–2186. doi: 10.1038/s41388-022-02238-5. DOI: https://doi.org/10.1038/s41388-022-02238-5
24- Roerden M, Spranger S. Cancer immune evasion, immunoediting and intratumour heterogeneity. Nat Rev Immunol. 2025;25:353–369. doi:10.1038/s41577-024-01111-8. DOI: https://doi.org/10.1038/s41577-024-01111-8
25- Lee, J., Roberts, J. S., Atanasova, K. R., Chowdhury, N., and Yilmaz, Ö. A. (2018). Novel kinase function of a nucleoside-diphosphate-kinase homologue in Porphyromonas gingivalis is critical in subversion of host cell apoptosis by targeting heat-shock protein 27. Cell Microbiol. 20:e12825. doi: 10.1111/cmi. 12825. DOI: https://doi.org/10.1111/cmi.12825
26- Jiang, S., Zhang, S., Langenfeld, J., Lo, S. C., and Rogers, M. B. (2008). Mycoplasma infection transforms normal lung cells and induces bone morphogenetic protein 2 expression by post-transcriptional mechanisms. J. Cell Biochem. 104, 580–594. doi: 10.1002/jcb.21647. DOI: https://doi.org/10.1002/jcb.21647
27- Alizadeh, S., Esmaeili, A., and Omidi, Y. (2020). Anti-cancer properties of Escherichia coli Nissle 1917 against HT-29 colon cancer cells through regulation of Bax/Bcl-xL and AKT/PTEN signaling pathways. Iran J. Basic Med. Sci. 23, 886–893. doi: 10.22038/ijbms.2020.43016.10115.
28- de Jesus, B. B., and Blasco, M. A. (2013). Telomerase at the intersection of cancer and aging. Trends Genet TIG. 29, 513–520. doi: 10.1016/j.tig.2013.06.007. DOI: https://doi.org/10.1016/j.tig.2013.06.007
29- Vliet-Gregg, P. A., Robinson, K. L., Levan, J., Matsumoto, L. R., and Katzenellenbogen, R. A. (2019). NFX1-123 is highly expressed in cervical cancer and increases growth and telomerase activity in HPV 16E6 expressing cells. Cancer Lett. 449, 106–113. doi: 10.1016/j.canlet.2019.02.024. DOI: https://doi.org/10.1016/j.canlet.2019.02.024
30- Liu X, Zhang J, Yi T, Li H, Tang X, Liu D, et al. Decoding tumor angiogenesis: pathways, mechanisms, and future directions in anti-cancer strategies. Biomark Res. 2025;13:62. doi:10.1186/s40364-025-00779-x. DOI: https://doi.org/10.1186/s40364-025-00779-x
31- Castro, P. R., Bittencourt, L. F. F., Larochelle, S., Andrade, S. P., Mackay, C. R., Slevin, M., et al. (2021). GPR43 regulates sodium butyrate-induced angiogenesis and matrix remodeling. Am. J. Physiol. Heart Circ. Physiol. 320, H1066–H1079. doi: 10.1152/ajpheart.00515.2019. DOI: https://doi.org/10.1152/ajpheart.00515.2019
32- Kuhn, K. A., Schulz, H. M., Regner, E. H., Severs, E. L., Hendrickson, J. D., Mehta, G., et al. (2018). Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity. Mucosal. Immunol. 11, 357–368. doi: 10.1038/mi.2017.55. DOI: https://doi.org/10.1038/mi.2017.55
33- Mantovani, A., Cassatella, M. A., Costantini, C., and Jaillon, S. (2011). Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 11, 519–531. doi: 10.1038/nri3024. DOI: https://doi.org/10.1038/nri3024
34- Kostic, A. D., Chun, E., Robertson, L., Glickman, J. N., Gallini, C. A., Michaud, M., et al. (2013). Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor immune microenvironment. Cell Host Microbe. 14, 207–215. doi: 10.1016/j.chom.2013.07.007. DOI: https://doi.org/10.1016/j.chom.2013.07.007
35- Coussens, L. M., and Pollard, J. W. (2011). Leukocytes in mammary development and cancer. Cold Spring Harb Perspect. Biol. 3:a003285. doi: 10.1101/cshperspect.a003285. DOI: https://doi.org/10.1101/cshperspect.a003285
36- Li, Z. P., Liu, J. X., Lu, L. L., Wang, L. L., Xu, L., Guo, Z. H., et al. (2021). Overgrowth of Lactobacillus in gastric cancer. World J. Gastrointest. Oncol. 13, 1099–1108. doi: 10.4251/wjgo.v13.i9.1099. DOI: https://doi.org/10.4251/wjgo.v13.i9.1099
37- Allgayer, H., Mahapatra, S., Mishra, B., Swain, B., Saha, S., Khanra, S.,et al. (2025). Epithelial-to-mesenchymal transition (EMT) and cancer metastasis: the status quo of methods and experimental models. Mol. Cancer 24:167. doi: 10.1186/s12943-025-02338-2. DOI: https://doi.org/10.1186/s12943-025-02338-2
38- Slater, E., Owen, R. J., Williams, M., and Pounder, R. E. (1999). Conservation of the cag pathogenicity island of Helicobacter pylori: associations with vacuolating cytotoxin allele and IS605 diversity. Gastroenterology 117, 1308–1315. doi: 10.1016/S0016-5085(99)70281-7. DOI: https://doi.org/10.1016/S0016-5085(99)70281-7
39- Yamaoka, Y. (2010). Mechanisms of disease: Helicobacter pylori virulence factors. Nat. Rev. Gastroenterol. Hepatol. 7, 629–641. doi: 10.1038/nrgastro.2010.154. DOI: https://doi.org/10.1038/nrgastro.2010.154
40- Shi, Y., Yang, Z., Zhang, T., Shen, L., Li, Y., and Ding, S. (2019). SIRT1-targeted miR-543 autophagy inhibition and epithelial-mesenchymal transition promotion in Helicobacter pylori CagA-associated gastric cancer. Cell Death Dis. 10:625. doi: 10.1038/s41419-019-1859-8. DOI: https://doi.org/10.1038/s41419-019-1859-8
41- Sommariva, M., and Gagliano, N. (2020). E-cadherin in pancreatic ductal adenocarcinoma: a multifaceted actor during EMT. Cells 9:1040. doi: 10.3390/cells9041040. DOI: https://doi.org/10.3390/cells9041040
42- Rubinstein, M. R., Wang, X., Liu, W., Hao, Y., Cai, G., and Han, Y. W. (2013). Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe. 14, 195–206. doi: 10.1016/j.chom.2013.07.012. DOI: https://doi.org/10.1016/j.chom.2013.07.012
43- Yu, J., Liang, Y., Zhang, Q., Ding, H., Xie, M., Zhang, J., et al. (2025). An interplay between human genetics and intratumoral microbiota in the progression of colorectal cancer. Cell Host Microbe. 33, 657–670.e6. doi: 10.1016/j.chom.2025.04.003. DOI: https://doi.org/10.1016/j.chom.2025.04.003
44- Zhang, Q., Zhao, Q., Li, T., Lu, L., Wang, F., Zhang, H., et al. (2023). Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8+ T cell immunity. Cell Metab. 35, 943–960.e9. doi: 10.1016/j.cmet.2023.04.015. DOI: https://doi.org/10.1016/j.cmet.2023.04.015
45- Nakashima, C., Yamamoto, K., Kishi, S., Sasaki, T., Ohmori, H., Fujiwara- Tani, R., et al. (2020). Clostridium perfringens enterotoxin induces claudin- 4 to activate YAP in oral squamous cell carcinomas. Oncotarget 11, 309–321. doi: 10.18632/oncotarget.27424. DOI: https://doi.org/10.18632/oncotarget.27424
46- Kong, C., Yan, X., Zhu, Y., Zhu, H., Luo, Y., Liu, P., et al. (2021). Fusobacterium nucleatum promotes the development of colorectal cancer by activating a cytochrome P450/epoxyoctadecenoic acid axis via TLR4/Keap1/NRF2 signaling. Cancer Res. 81, 4485–4498. doi: 10.1158/0008-5472.CAN-21-0453. DOI: https://doi.org/10.1158/0008-5472.CAN-21-0453
47- Parida, S., Wu, S., Siddharth, S.,Wang, G., Muniraj, N.,Nagalingam, A., et al. (2021). A procarcinogenic colon microbe promotes breast tumorigenesis and metastatic progression and concomitantly activates notch and β-catenin axes. Cancer Discov. 11, 1138–1157. doi: 10.1158/2159-8290.CD-20-0537. DOI: https://doi.org/10.1158/2159-8290.CD-20-0537
48- Fu, A., Yao, B., Dong, T., Chen, Y., Yao, J., Liu, Y., et al. (2022). Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell 185, 1356–1372.e26. doi: 10.1016/j.cell.2022.02.027. DOI: https://doi.org/10.1016/j.cell.2022.02.027
49- Chen Y, Liu S, Tan S, Zheng Y, Chen Y, Yang C, et al. KRAS mutations promote the intratumoral colonization of enterotoxigenic Bacteroides fragilis in colorectal cancer through the regulation of the miRNA3655/SURF6/IRF7/IFNβ axis. Gut Microbes. 2024;16:2423043. doi:10.1080/19490976.2024.2423043. DOI: https://doi.org/10.1080/19490976.2024.2423043
50- Zheng, X., Liu, R., Zhou, C., Yu, H., Luo, W., Zhu, J., et al. (2021). ANGPTL4-mediated promotion of glycolysis facilitates the colonization of Fusobacterium nucleatum in colorectal cancer. Cancer Res. 81, 6157–6170. doi: 10.1158/0008-5472.CAN-21-2273. DOI: https://doi.org/10.1158/0008-5472.CAN-21-2273
51- Hong, J., Guo, F., Lu, S. Y., Shen, C., Ma, D., Zhang, X., et al. (2021). F. nucleatum targets lncRNA ENO1-IT1 to promote glycolysis and oncogenesis in colorectal cancer. Gut 70, 2123–2137. doi: 10.1136/gutjnl-2020-322780. DOI: https://doi.org/10.1136/gutjnl-2020-322780
52- Sun, J., Tang, Q., Yu, S., Xie, M., Zheng, W., Chen, G., et al. (2023). F. nucleatum facilitates oral squamous cell carcinoma progression via GLUT1-driven lactate production. eBioMedicine 88:104444. doi: 10.1016/j.ebiom.2023.104444. DOI: https://doi.org/10.1016/j.ebiom.2023.104444
53- Berrios, C., Padi, M., Keibler, M. A., Park, D. E., Molla, V., Cheng, J., et al. (2016). Merkel cell polyomavirus small T antigen promotes pro-glycolytic metabolic perturbations required for transformation. PLoS Pathog. 12:e1006020. doi: 10.1371/journal.ppat.1006020. DOI: https://doi.org/10.1371/journal.ppat.1006020
54- Tzeng, A., Sangwan, N., Jia, M., Liu, C. C., Keslar, K. S., Downs-Kelly, E., et al. (2021). Human breast microbiome correlates with prognostic features and immunological signatures in breast cancer. Genome Med. 13:60. doi: 10.1186/s13073-021-00874-2. DOI: https://doi.org/10.1186/s13073-021-00874-2
55- Mima, K., Sukawa, Y., Nishihara, R., Qian, Z. R., Yamauchi, M., Inamura, K., et al. (2015). Fusobacterium nucleatum and T-cells in colorectal carcinoma. JAMA Oncol. 1, 653–661. doi: 10.1001/jamaoncol.2015.1377. DOI: https://doi.org/10.1001/jamaoncol.2015.1377
56- Wang, Q., Liu, Y., Chen, W., Chen, S., Su, M., Zheng, Y., et al. (2024). Uterine commensal peptostreptococcus species contribute to ido1 induction in endometrial cancer via indoleacrylic acid. Biomedicines 12:573. doi: 10.3390/biomedicines12030573. DOI: https://doi.org/10.3390/biomedicines12030573
57- Sui, H., Zhang, L., Gu, K., Chai, N., Ji, Q., Zhou, L., et al. (2020). YYFZBJS ameliorates colorectal cancer progression in ApcMin/+ mice by remodeling gut microbiota and inhibiting regulatory T-cell generation. Cell Commun. Signal CCS 18:113. doi: 10.1186/s12964-020-00596-9. DOI: https://doi.org/10.1186/s12964-020-00596-9
58- Shi, Y., Zheng,W., Yang, K., Harris, K. G., Ni, K., Xue, L., et al. (2020). Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling. J. Exp. Med. 217:e20192282. doi: 10.1084/jem.20192282. DOI: https://doi.org/10.1084/jem.20192282
59- Overacre-Delgoffe, A. E., Bumgarner, H. J., Cillo, A. R., Burr, A. H. P., Tometich, J. T., Bhattacharjee, A., et al. (2021). Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer. Immunity 54, 2812–2824.e4. doi: 10.1016/j.immuni.2021.11.003. DOI: https://doi.org/10.1016/j.immuni.2021.11.003
60- Davar D, Dzutsev AK, McCulloch JA, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021;371(6529):595–602. doi:10.1126/science.abf3363. DOI: https://doi.org/10.1126/science.abf3363
61- Martínez-Jiménez, F., Muiños, F., Sentís, I., Deu-Pons, J., Reyes-Salazar, I., Arnedo- Pac, C., et al. (2020). A compendium of mutational cancer driver genes. Nat. Rev. Cancer 20, 555–572. doi: 10.1038/s41568-020-0290-x. DOI: https://doi.org/10.1038/s41568-020-0290-x
62- Lim, N. R., and Chung, W. C. (2023). Helicobacter pylori-associated chronic atrophic gastritis and progression of gastric carcinogenesis. Korean J. Gastroenterol. Taehan Sohwagi Hakhoe Chi. 82, 171–179. doi: 10.4166/kjg.2023.097. DOI: https://doi.org/10.4166/kjg.2023.097
63- Cao, Y., Oh, J., Xue, M., Huh, W. J., Wang, J., Gonzalez-Hernandez, J. A., et al. (2022). Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites. Science 378:eabm3233. doi: 10.1126/science.abm3233. DOI: https://doi.org/10.1126/science.abm3233
64- Okuda, S., Shimada, Y., Tajima, Y., Yuza, K., Hirose, Y., Ichikawa, H., et al. (2021). Profiling of host genetic alterations and intra-tumor microbiomes in colorectal cancer. Comput. Struct. Biotechnol. J. 19, 3330–3338. doi: 10.1016/j.csbj.2021.05.049. DOI: https://doi.org/10.1016/j.csbj.2021.05.049
65- Giam CZ, Semmes OJ. HTLV-1 infection and adult T-cell leukemia/lymphoma: a tale of two proteins, Tax and HBZ. Viruses. 2016;8:161. doi:10.3390/v8060161. DOI: https://doi.org/10.3390/v8060161
66- Guo, P., Tian, Z., Kong, X., Yang, L., Shan, X., Dong, B., et al. (2020). FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2. J. Exp. Clin. Cancer Res. CR. 39:202. doi: 10.1186/s13046-020-01677-w. DOI: https://doi.org/10.1186/s13046-020-01677-w
67- Pushalkar S, Hundeyin M, Daley D, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 2018;8:403–416. doi:10.1158/2159-8290.CD-17-1134. DOI: https://doi.org/10.1158/2159-8290.CD-17-1134
68- Pleguezuelos-Manzano, C., Puschhof, J., Rosendahl Huber, A., van Hoeck, A., Wood, H. M., Nomburg, J., et al. (2020). Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature 580, 269–273. doi: 10.1038/s41586-020-2080-8. DOI: https://doi.org/10.1038/s41586-020-2080-8
69- Robles, A. I., and Harris, C. C. (2010). Clinical outcomes and correlates of TP53 mutations and cancer. Cold Spring Harb. Perspect. Biol. 2:a001016. doi: 10.1101/cshperspect.a001016. DOI: https://doi.org/10.1101/cshperspect.a001016
70- Greathouse, K. L., White, J. R., Vargas, A. J., Bliskovsky, V. V., Beck, J. A., von Muhlinen, N., et al. (2018). Interaction between the microbiome and TP53 in human lung cancer. Genome Biol. 19:123. doi: 10.1186/s13059-018-1501-6. DOI: https://doi.org/10.1186/s13059-018-1501-6
71- Denk, D., and Greten, F. R. (2022). Inflammation: the incubator of the tumor microenvironment. Trends Cancer 8, 901–914. doi: 10.1016/j.trecan.2022.07.002. DOI: https://doi.org/10.1016/j.trecan.2022.07.002
72- DiDonato, J. A., Mercurio, F., and Karin, M. (2012). NF-κB and the link between inflammation and cancer. Immunol. Rev. 246, 379–400. doi: 10.1111/j.1600-065X.2012.01099.x. DOI: https://doi.org/10.1111/j.1600-065X.2012.01099.x
73- Hoste, E., Arwert, E. N., Lal, R., South, A. P., Salas-Alanis, J. C., Murrell, D. F., et al.(2015). Innate sensing of microbial products promotes wound-induced skin cancer. Nat. Commun. 6:5932. doi: 10.1038/ncomms6932. DOI: https://doi.org/10.1038/ncomms6932
74- Goodwin, A. C., Destefano Shields, C. E., Wu, S., Huso, D. L., Wu, X., Murray- Stewart, T. R., et al. (2011). Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc. Natl. Acad. Sci. U. S. A. 108, 15354–15359. doi: 10.1073/pnas.1010203108. DOI: https://doi.org/10.1073/pnas.1010203108
75- Dejea, C. M., Fathi, P., Craig, J. M., Boleij, A., Taddese, R., Geis, A. L., et al. (2018). Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592–597. doi: 10.1126/science.aah3648. DOI: https://doi.org/10.1126/science.aah3648
76- Mou, W., Deng, Z., Zhu, L., Jiang, A., Lin, A., Xu, L., et al. (2025). Intratumoral mycobiome heterogeneity influences the tumor microenvironment and immunotherapy outcomes in renal cell carcinoma. Sci. Adv. 11:eadu1727. doi: 10.1126/sciadv.adu1727. DOI: https://doi.org/10.1126/sciadv.adu1727
77- Narunsky-Haziza, L., Sepich-Poore, G. D., Livyatan, I., Asraf, O., Martino, C., Nejman, D., et al. (2022). Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell 185, 3789–3806.e17. doi: 10.1016/j.cell.2022.09.005. DOI: https://doi.org/10.1016/j.cell.2022.09.005
78- Liang, Y., Li, Q., Liu, Y., Guo, Y., and Li, Q. (2023). Awareness of intratumoral bacteria and their potential application in cancer treatment. Discov. Oncol. 14:57. doi: 10.1007/s12672-023-00670-x. DOI: https://doi.org/10.1007/s12672-023-00670-x
79- López-Otín, C., and Kroemer, G. (2021). Hallmarks of health. Cell 184, 33–63. doi: 10.1016/j.cell.2020.11.034. DOI: https://doi.org/10.1016/j.cell.2020.11.034
80- Park, E. M., Chelvanambi, M., Bhutiani, N., Kroemer, G., Zitvogel, L., and Wargo, J. A. (2022). Targeting the gut and tumor microbiota in cancer. Nat. Med. 28, 690–703. doi: 10.1038/s41591-022-01779-2. DOI: https://doi.org/10.1038/s41591-022-01779-2
81- Png, C. W., Lee,W. J. J., Chua, S. J., Zhu, F., Gastric Consortium5, Yeoh, K. G., and Zhang, Y. (2022). Mucosal microbiome associates with progression to gastric cancer. Theranostics 12, 48–58. doi: 10.7150/thno.65302. DOI: https://doi.org/10.7150/thno.65302
82- Geller, L. T., Barzily-Rokni, M., Danino, T., Jonas, O. H., Shental, N., Nejman, D., et al. (2017). Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357, 1156–1160. doi: 10.1126/science.aah5043. DOI: https://doi.org/10.1126/science.aah5043
83- Yu, T., Guo, F., Yu, Y., Sun, T., Ma, D., Han, J., et al. (2017). Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 170, 548–563.e16. doi: 10.1016/j.cell.2017.07.008. DOI: https://doi.org/10.1016/j.cell.2017.07.008
84- Yang, W., Chen, C. H., Jia, M., Xing, X., Gao, L., Tsai, H. T., et al. (2021). Tumorassociated microbiota in esophageal squamous cell carcinoma. Front. Cell Dev. Biol. 9:641270. doi: 10.3389/fcell.2021.641270. DOI: https://doi.org/10.3389/fcell.2021.641270
85- Liu, J., and Zhang, Y. (2022). Intratumor microbiome in cancer progression: current developments, challenges and future trends. Biomark. Res. 10:37. doi: 10.1186/s40364-022-00381-5. DOI: https://doi.org/10.1186/s40364-022-00381-5
86- Gao, S., Li, S., Ma, Z., Liang, S., Shan, T., Zhang, M., et al. (2016). Presence of Porphyromonas gingivalis in esophagus and its association with the clinicopathological characteristics and survival in patients with esophageal cancer. Infect. Agent Cancer 11:3. doi: 10.1186/s13027-016-0049-x. DOI: https://doi.org/10.1186/s13027-016-0049-x
87- Liu, C. J., Chen, S. Q., Zhang, S. Y., Wang, J. L., Tang, X. D., Yang, K. X., et al. (2021). The comparison of microbial communities in thyroid tissues from thyroid carcinoma patients. J. Microbiol. Seoul Korea 59, 988–1001. doi: 10.1007/s12275-021-1271-9. DOI: https://doi.org/10.1007/s12275-021-1271-9
88- Xu, L., Hu, B., He, J., Fu, X., and Liu, N. (2025). Intratumor microbiomederived butyrate promotes chemo-resistance in colorectal cancer. Front. Pharmacol. 15:1510851. doi: 10.3389/fphar.2024.1510851. DOI: https://doi.org/10.3389/fphar.2024.1510851
89- Westman, E. L., Canova, M. J., Radhi, I. J., Koteva, K., Kireeva, I., Waglechner, N., et al. (2012). Bacterial inactivation of the anticancer drug doxorubicin. Chem. Biol. 19, 1255–1264. doi: 10.1016/j.chembiol.2012.08.011. DOI: https://doi.org/10.1016/j.chembiol.2012.08.011
90- Yan, A., Culp, E., Perry, J., Lau, J. T., MacNeil, L. T., Surette, M. G., et al. (2018). Transformation of the anticancer drug doxorubicin in the human gutmicrobiome. ACS Infect. Dis. 4, 68–76. doi: 10.1021/acsinfecdis.7b00166. DOI: https://doi.org/10.1021/acsinfecdis.7b00166
91- Miller, B. C., Sen, D. R., Al Abosy, R., Bi, K., Virkud, Y. V., LaFleur, M. W., et al. (2019). Author correction: subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20:1556. doi: 10.1038/s41590-019-0528-5. DOI: https://doi.org/10.1038/s41590-019-0528-5
92- Yang, L., Wang, Q., He, L., and Sun, X. (2024). The critical role of tumor microbiome in cancer immunotherapy. Cancer Biol Ther. 25:2301801. doi: 10.1080/15384047.2024.2301801. DOI: https://doi.org/10.1080/15384047.2024.2301801
93- Sivan, A., Corrales, L., Hubert, N., Williams, J. B., Aquino-Michaels, K., Earley, Z. M., et al. (2015). Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089. doi: 10.1126/science.aac4255. DOI: https://doi.org/10.1126/science.aac4255
94- Yang, P., Liang, G., Ni, Y., Chu, X., Zhang, X.,Wang, Z., et al. (2025). Investigating the role of intratumoral Streptococcus mitis in gastric cancer progression: insights into tumor microenvironment. J. Transl. Med. 23:126. doi: 10.1186/s12967-025-06142-w. DOI: https://doi.org/10.1186/s12967-025-06142-w
95- Abe, S., Masuda, A., Matsumoto, T., Inoue, J., Toyama, H., Sakai, A., et al. (2024). Impact of intratumoral microbiome on tumor immunity and prognosis in human pancreatic ductal adenocarcinoma. J. Gastroenterol. 59, 250–262. doi: 10.1007/s00535-023-02069-5. DOI: https://doi.org/10.1007/s00535-023-02069-5
96- Bender MJ, McPherson AC, Phelps CM, et al. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Cell. 2023;186:1846–1862.e26. doi:10.1016/j.cell.2023.03.018. DOI: https://doi.org/10.1016/j.cell.2023.03.011
97- Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104–108. doi:10.1126/science.aao3290. DOI: https://doi.org/10.1126/science.aao3290
98- Chen, Y., Yang, L., Huang, Y., Zhu, T., Zhang, L., Cheng, M., et al. (2025). Intratumoral microbiota predicts the response to neoadjuvant chemoimmunotherapy in triple-negative breast cancer. J. Immunother. Cancer 13:e010365. doi: 10.1136/jitc-2024-010365. DOI: https://doi.org/10.1136/jitc-2024-010365
99- Xie, Y., Xie, F., Zhou, X., Zhang, L., Yang, B., Huang, J., et al. (2022). Microbiota in tumors: from understanding to application. Adv. Sci. Weinh Baden-Wurtt Ger. 9:e2200470. doi: 10.1002/advs.202200470. DOI: https://doi.org/10.1002/advs.202200470
100- Chowdhury, S., Castro, S., Coker, C., Hinchliffe, T. E., Arpaia, N., and Danino, T. (2019). Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat. Med. 25, 1057–1063. doi: 10.1038/s41591-019-0498-z. DOI: https://doi.org/10.1038/s41591-019-0498-z
101- Gurbatri, C. R., Lia, I., Vincent, R., Coker, C., Castro, S., Treuting, P.M., et al. (2020). Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies. Sci. Transl. Med. 12:eaax0876. doi: 10.1126/scitranslmed.aax0876. DOI: https://doi.org/10.1126/scitranslmed.aax0876
102- Murphy, C., Rettedal, E., Lehouritis, P., Devoy, C., and Tangney, M. (2017). Intratumoural production of TNFα by bacteria mediates cancer therapy. PLoS One 12:e0180034. doi: 10.1371/journal.pone.0180034. DOI: https://doi.org/10.1371/journal.pone.0180034
103- Zheng, J. H., Nguyen, V. H., Jiang, S. N., Park, S. H., Tan, W., Hong, S. H., et al. (2017). Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin. Sci Transl Med. 9, eaak9537. doi: 10.1126/scitranslmed.aak9537. DOI: https://doi.org/10.1126/scitranslmed.aak9537
104- Young LS, Yap LF, Murray PG. Epstein–Barr virus: more than 50 years old and still providing surprises. Nat Rev Cancer. 2016;16:789–802. doi:10.1038/nrc.2016.92. DOI: https://doi.org/10.1038/nrc.2016.92
105- Ringelhan M, McKeating JA, Protzer U. Viral hepatitis and liver cancer. Philos Trans R Soc Lond B Biol Sci. 2017;372:20160274. doi:10.1098/rstb.2016.0274. DOI: https://doi.org/10.1098/rstb.2016.0274
106- Gessain A, Cassar O. Epidemiological aspects and world distribution of HTLV-1 infection. Front Microbiol. 2012;3:388. doi:10.3389/fmicb.2012.00388. DOI: https://doi.org/10.3389/fmicb.2012.00388
107- Becker JC, Stang A, DeCaprio JA, et al. Merkel cell carcinoma. Nat Rev Dis Primers. 2017;3:17077. doi:10.1038/nrdp.2017.77. DOI: https://doi.org/10.1038/nrdp.2017.77
108- Parikh HI, Koparde VN, Bradley SP, et al. The intratumoral microbiome and cancer. Cancer Res. 2024.
Additional Files
Received
Revised
Accepted
Published
Data Availability Statement
No new datasets were generated or analyzed during this study. All information discussed in this review was obtained from previously published articles cited in the reference list.
Issue
Section
License
Copyright (c) 2026 Iraqi Journal of Cancer and Medical Genetics
This work is licensed under a Creative Commons Attribution 4.0 International License.
