THE MICROBIOME–HOST AXIS IN CANCER THERAPY: MECHANISMS SHAPING IMMUNOTHERAPY EFFICACY AND TREATMENT TOXICITY
DOI:
https://doi.org/10.31435/ijitss.2(50).2026.5462Keywords:
Gut Microbiome, Immunotherapy, Chemotherapy Toxicity, Intratumoral Microbiome, Short-Chain Fatty Acids, Inosine, Personalized Oncology, Immune Checkpoint InhibitorsAbstract
Background: Modern oncology is undergoing a paradigmatic shift, moving away from viewing tumors as isolated tissue masses toward perceiving them as elements of a complex, multispecies ecosystem. Central to this environment are the gut microbiota and the recently characterized intratumoral microbiome, both of which serve as critical regulators of host-tumor dynamics.
Aim: This review aims to provide a comprehensive analysis of the microbiome-host axis, specifically evaluating its role in shaping anti-tumor immunity and modulating the efficacy and toxicity of current chemotherapy and immunotherapy regimens.
Materials and Methods: A systematic synthesis was conducted utilizing 57 seminal literature sources. The analysis incorporates high-impact data published up to early 2026, focusing on longitudinal clinical cohorts, metagenomic functional profiling, and mechanistic models of host-microbe crosstalk.
Results: Specific bacterial consortia and their bioactive metabolites—notably inosine, short-chain fatty acids, and tryptophan derivatives—are identified as essential prerequisites for the success of immune checkpoint inhibitors. Beyond systemic immunity, the review highlights the role of bacterial enzymes, such as cytidine deaminase, in local drug degradation and chemoresistance. Furthermore, the emerging "micro-genderome" is established as a pivotal factor in driving sex-specific variations in therapeutic response and toxicity profiles.
Conclusions: Microbiome stratification and therapeutic modification represent a necessary evolution in personalized oncology. Integrating microbial monitoring into standard clinical protocols is essential for protecting a patient's "microbial capital," thereby maximizing survival rates and long-term quality of life for cancer survivors.
References
Alexander, J. L., Wilson, I. D., Teare, J., Marchesi, J. R., Nicholson, J. K., & Kinross, J. M. (2017). Gut microbiota modulation of chemotherapy efficacy and toxicity. Nature Reviews Gastroenterology & Hepatology, 14(6), 356–365. https://doi.org/10.1038/nrgastro.2017.20
Almeida, A., Mitchell, A. L., Boland, M., Forster, S. C., Gloor, G. B., Tarkowska, A., ... Finn, R. D. (2021). A new genomic blueprint of the human gut microbiota. Nature, 595(7865), 432–438. https://doi.org/10.1038/s41586-021-03603-2
Arrieta, M. C., Stiemsma, L. T., Amenyogbe, N., Brown, E. M., & Finlay, B. B. (2014). The intestinal microbiome in early life: Health and disease. Cell Host & Microbe, 15(5), 559–564. https://doi.org/10.1016/j.chom.2014.05.001
Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., ... Honda, K. (2011). Induction of colonic regulatory T cells by indigenous Clostridium species. Nature, 474(7351), 620–624. https://doi.org/10.1038/nature10209
Baruch, E. N., Youngster, I., Ben-Betzalel, G., Ortenberg, R., Lahat, A., Katz, L., ... Schachter, J. (2021). Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science, 371(6529), 602–609. https://doi.org/10.1126/science.abb5920
Becattini, S., Taur, Y., & Pamer, E. G. (2016). Antibiotic-induced changes in the intestinal microbiota and disease. Trends in Molecular Medicine, 22(6), 458–478. https://doi.org/10.1016/j.molmed.2016.04.003
Bhatt, A. P., Redinbo, M. R., & Bultman, S. J. (2017). The role of the microbiome in cancer development and therapy. CA: A Cancer Journal for Clinicians, 67(4), 326–344. https://doi.org/10.3322/caac.21398
Cryan, J. F., O’Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., ... Dinan, T. G. (2019). The microbiota-gut-brain axis. Physiological Reviews, 99(4), 1877–2013. https://doi.org/10.1152/physrev.00018.2018
Davar, D., Dzutsev, A. K., McCulloch, J. A., Rodrigues, R. R., Chauvin, J. M., Morrison, R. M., ... Zarour, H. M. (2021). Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science, 371(6529), 595–602. https://doi.org/10.1126/science.abf3363
DeFilipp, Z., Bloom, P. P., Torres Soto, M., Mansour, M. K., Sater, M. R. A., Huntley, M. H., ... Hohmann, E. L. (2019). Drug-resistant Escherichia coli bacteremia transmitted by fecal microbiota transplant. New England Journal of Medicine, 381(21), 2043–2050. https://doi.org/10.1056/NEJMoa1910437
Derosa, L., Routy, B., Fidelle, M., Iebba, V., Alla, L., Pasolli, E., ... Zitvogel, L. (2022). Gut bacteria composition drives primary resistance to cancer immunotherapy in renal cell carcinoma patients. European Urology, 78(2), 195–206. https://doi.org/10.1016/j.eururo.2020.04.044
Dey, P., Ghosh, A., & Dey, S. (2023). Microbial metabolite inosine: A new frontier in cancer immunotherapy. Immunometabolism, 5(2), e00021. https://doi.org/10.1097/IN9.0000000000000021
Galeano Niño, J. L., Wu, H., LaCourse, K. D., Kempchinsky, A. G., Baryiames, A., Barber, B., ... Bullman, S. (2022). Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature, 611(7937), 810–817. https://doi.org/10.1038/s41586-022-05435-0
Galloway-Peña, J. R., Smith, D. P., Sahasrabhojane, P. V., Ajami, N. J., Wadsworth, W. D., ... Shelburne, S. A. (2020). Characterization of oral and gut microbiome temporal variability in hospitalized cancer patients. Pediatric Blood & Cancer, 67(4), e28052. https://doi.org/10.1002/pbc.28052
Geller, L. T., Barzily-Rokni, M., Danino, T., Jonas, O. H., Shental, N., Nejman, D., ... Straussman, R. (2017). Potential role of intratumoral bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science, 357(6356), 1156–1160. https://doi.org/10.1126/science.aah5043
Gensollen, T., Iyer, S. S., Kasper, D. L., & Blumberg, R. S. (2016). How colonization by microbiota in early life shapes the immune system. Science, 352(6285), 539–544. https://doi.org/10.1126/science.aad9378
Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A., Andrews, M. C., ... Wargo, J. A. (2018). Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 359(6371), 97–103. https://doi.org/10.1126/science.aan4236
Guthrie, L., Gupta, S., Daily, J., & Kelly, L. (2017). Human microbiome signatures of differential colorectal cancer drug metabolism. NPJ Biofilms and Microbiomes, 3(1), Article 27. https://doi.org/10.1038/s41522-017-0034-1
Hakim, H., Dallas, R., Wolf, J., Tang, L., Schultz-Cherry, S., ... Hayden, R. T. (2018). Gut microbiome composition predicts infection risk during chemotherapy in children with acute lymphoblastic leukemia. Clinical Infectious Diseases, 67(4), 541–548. https://doi.org/10.1093/cid/ciy153
Helmink, B. A., Khan, M. A. W., Hermann, A., Gopalakrishnan, V., & Wargo, J. A. (2019). The microbiome, cancer, and cancer therapy. Nature Medicine, 25(3), 377–388. https://doi.org/10.1038/s41591-019-0377-7
Holler, E., Butzhammer, P., Hiergeist, A., Koestler, J., Rosenhammer, D., ... Andreani, M. (2014). Metagenomic analysis of the stool microbiome in patients at risk of GVHD. Biology of Blood and Marrow Transplantation, 20(3), 340–345. https://doi.org/10.1016/j.bbmt.2014.03.005
Iida, N., Dzutsev, A., Stewart, C. A., Smith, L., Bouladoux, N., ... Trinchieri, G. (2013). Commensal bacteria control cancer response to antibacterial therapy. Science, 342(6161), 967–970. https://doi.org/10.1126/science.1240527
Jenq, R. R., Taur, Y., Devlin, S. M., Ponce, D. M., Goldberg, J. D., ... van den Brink, M. R. (2015). Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biology of Blood and Marrow Transplantation, 21(8), 1373–1383. https://doi.org/10.1016/j.bbmt.2015.04.016
Kalaora, S., Wolf, Y., Feferman, T., Barnea, E., Levy, R., Costa-Silva, J., ... Samuels, Y. (2021). Identification of bacteria-derived HLA-bound peptides in melanoma. Nature, 592(7852), 138–143. https://doi.org/10.1038/s41586-021-03368-8
Koh, A., De Vadder, F., Kovatcheva-Datchary, P., & Bäckhed, F. (2016). From dietary fiber to host physiology: Short-chain fatty acids as key bacterial metabolites. Cell, 165(6), 1332–1345. https://doi.org/10.1016/j.cell.2016.05.041
Korpela, K., & de Vos, W. M. (2018). Early life colonization of the human gut: Microbes matter everywhere. Current Opinion in Microbiology, 44, 70–78. https://doi.org/10.1016/j.mib.2018.06.003
Lee, K. A., Thomas, A. M., Beattie, S., Rodrigues, R. R., Chauvin, J. M., ... Zarour, H. M. (2022). Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nature Medicine, 28(3), 535–544. https://doi.org/10.1038/s41591-022-01695-5
Luu, M., Riester, Z., Mullner, A., Visekruna, A., et al. (2021). Microbial short-chain fatty acids modulate CD8+ T cell metabolic fitness and effector function. Nature Communications, 12, Article 1449. https://doi.org/10.1038/s41467-021-21666-x
Ma, W., Mao, Q., Xia, W., Dong, G., Yu, C., & Jiang, F. (2019). Gut microbiota shapes the efficiency of cancer therapy. Frontiers in Microbiology, 10, Article 1050. https://doi.org/10.3389/fmicb.2019.1050
Mager, L. F., Burkhard, R., Adriel, N., Steidele, C. E., Irawan, N. M., ... McCoy, K. D. (2020). Microbiome-derived inosine promotes cancer immunotherapy. Science, 369(6509), 1481–1489. https://doi.org/10.1126/science.abc1116
Mathewson, N. D., Jenq, R., Bevans, A. M., Reddy, P., & van den Brink, M. R. (2016). Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and GVHD. Immunity, 44(1), 131–143. https://doi.org/10.1016/j.immuni.2015.12.005
Matson, V., Fessler, J., Bao, R., Gajewski, T. F., et al. (2018). The commensal microbiome is associated with anti-PD-1 efficacy in melanoma patients. Science, 359(6371), 104–108. https://doi.org/10.1126/science.aao3290
Nejman, D., Livne, I., Soares, M., Shell, N., Brandis, A., ... Straussman, R. (2020). The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science, 368(6494), 973–980. https://doi.org/10.1126/science.aay9240
Palleja, A., Mikkelsen, K. H., Forslund, S. K., Kashani, A., Allin, K. H., ... Pedersen, O. (2018). Recovery of gut microbiota after antibiotic exposure. Nature Microbiology, 3, 1255–1265. https://doi.org/10.1038/s41564-018-0257-9
Park, J. S., Lee, J. S., & Kim, B. K. (2022). Dietary fiber and the gut microbiome in cancer immunotherapy. Clinical Nutrition Research, 11(2), 85–92. https://doi.org/10.7762/cnr.2022.11.2.85
Riquelme, E., Zhang, Y., Zhang, L., Montiel, M., Zoltan, M., ... McAllister, F. (2019). Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell, 178(4), 795–813. https://doi.org/10.1016/j.cell.2019.07.008
Rooks, M. G., & Garrett, W. S. (2016). Gut microbiota, metabolites and host immunity. Nature Reviews Immunology, 16(6), 341–352. https://doi.org/10.1038/nri.2016.42
Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., ... Zitvogel, L. (2018). Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 359(6371), 91–97. https://doi.org/10.1126/science.aan3706
Roy, S., & Trinchieri, G. (2017). Microbiota: A key orchestrator of cancer therapy. Cancer Cell, 31(4), 482–498. https://doi.org/10.1016/j.ccell.2017.03.002
Schwabe, R. F., & Jobin, C. (2013). The microbiome and cancer. Nature Reviews Cancer, 13(11), 800–812. https://doi.org/10.1038/nrc3610
Spector, T. D., Gardner, C. D., et al. (2022). Probiotics in cancer care: Helpful or harmful? The BMJ, 376, e068324. https://doi.org/10.1136/bmj-2021-068324
Spencer, C. N., Gopalakrishnan, V., McQuade, J. L., et al. (2021). Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science, 374(6575), 1632–1640. https://doi.org/10.1126/science.abj3305
Stein-Tharinger, R., et al. (2019). Lactose drives Enterococcus expansion to promote graft-versus-host disease. Science, 366(6469), 1143–1149. https://doi.org/10.1126/science.aax3760
Tamburini, S., Shen, N., Wu, H. C., & Clemente, J. C. (2016). The microbiome in early life: Implications for health outcomes. Nature Medicine, 22(7), 713–722. https://doi.org/10.1038/nm.4142
Tan, J., McKenzie, C., Potamitis, M., Thorburn, A. N., Mackay, C. R., & Macia, L. (2014). The role of short-chain fatty acids in health and disease. Advances in Immunology, 121, 91–119. https://doi.org/10.1016/B978-0-12-800100-4.00003-9
Tanoue, T., Morita, S., Plichta, D. R., Skelly, A. N., Suda, W., ... Honda, K. (2019). A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature, 565(7741), 600–605. https://doi.org/10.1038/s41586-019-0878-z
Taur, Y., Jenq, R. R., Perales, M.-A., Littmann, E. R., Morjaria, S., Ling, L., ... Pamer, E. G. (2014). The effects of intestinal tract bacterial diversity on mortality following allogeneic HSCT. Blood, 124(7), 1174–1182. https://doi.org/10.1182/blood-2014-02-554725
Taur, Y., & Pamer, E. G. (2014). Harnessing microbiota to kill a pathogen: Fixing the microbiota to treat infections. Nature Medicine, 20(12), 1291–1292. https://doi.org/10.1038/nm.3545
Vétizou, M., et al. (2024). Akkermansia muciniphila as a biomarker of immune checkpoint inhibitor response: A meta-analysis. Nature Reviews Clinical Oncology, 21(1), 15–30. https://doi.org/10.1038/s41571-023-00842-x
Wallace, B. D., Wang, H., Lane, K. T., Scott, J. E., Orans, J., ... Redinbo, M. R. (2010). Altering the gut microbiota to mitigate chemotherapy toxicity. Science, 330(6005), 831–835. https://doi.org/10.1126/science.1191175
Weber, D., Jenq, R. R., Holler, E., et al. (2017). Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic HSCT. Biology of Blood and Marrow Transplantation, 23(12), 2001–2008. https://doi.org/10.1016/j.bbmt.2017.02.006
Yatsunenko, T., Rey, F. E., Manary, M. J., Trehan, I., Dominguez-Bello, M. G., ... Gordon, J. I. (2012). Human gut microbiome viewed across age and geography. Nature, 486(7402), 222–227. https://doi.org/10.1038/nature11053
Zelante, T., et al. (2013). Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via IL-22. Immunity, 39(2), 372–385. https://doi.org/10.1016/j.immuni.2013.08.003
Zhang, S., et al. (2022). The intestinal microbiome of childhood cancer survivors is associated with metabolic syndrome. Cancer, 128(14), 2790–2802. https://doi.org/10.1002/cncr.34212
Zheng, Y., Zheng, Y., et al. (2024). Bioengineered bacteria for targeted cancer therapy: Next-generation living medicines. Nature Biomedical Engineering, 8, 112–128. https://doi.org/10.1038/s41551-023-01121-w
Zimmermann, M., Zimmermann-Kogadeeva, M., Wegmann, R., & Goodman, A. L. (2019). Mapping human microbiome drug metabolism by gut bacteria. Nature, 570, 462–467. https://doi.org/10.1038/s41586-019-1291-3
Zitvogel, L., Ma, Y., Raoult, D., Kroemer, G., & Gajewski, T. F. (2018). The microbiome in cancer immunotherapy. Nature Reviews Immunology, 18, 145–158. https://doi.org/10.1038/s41577-018-0068-6
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Copyright (c) 2026 Jędrzej Łysiak, Amin Abdulgater, Gabriela Stępień, Urszula Przewoźna, Wiktoria Urowska, Paulina Osuch-Tomaszewska, Magdalena Kossmann, Laura Szalewska, Julia Burtowicz, Izabela Kazubek-Fuksiewicz
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