Published December 22, 2025 | Version v1
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Microbiome and response to immunotherapy in malignant melanoma

Authors/Creators

  • 1. Medical University of Graz, Graz, Austria
  • 2. Medical University of Graz, Graz, Austria|Center for Biomarker Research in Medicine, Graz, Austria|BioTechMed-Graz, Graz, Austria

Description

Immune checkpoint inhibitors (ICIs) have improved survival in advanced melanoma; however, a considerable number of patients does not respond, and side effects are common. Studies suggest that the gut microbiome may influence ICI outcomes, with certain bacteria and microbial functions being linked to a positive response in some patient groups. However, findings are inconsistent across studies, and no universal microbial biomarkers have been identified. Longitudinal and multi-omic analyses indicate that microbial dynamics may matter, and that other body sites, such as the skin and the intratumoral environment, could also be relevant. More systematic research and testing of multiple hypotheses is needed before microbiome-based strategies may be reliably applied in clinical practice. Here, we summarize evidence connecting the human microbiome to ICI response in melanoma.

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Cites
Publication: 10.1056/NEJMoa1003466 (DOI)
Publication: 10.1056/NEJMoa1200694 (DOI)
Publication: 10.1056/NEJMoa2109970 (DOI)
Publication: 10.1056/NEJMoa2407417 (DOI)
Publication: 10.3390/cancers15133448 (DOI)
Publication: 10.1200/JCO.2016.72.1167 (DOI)
Publication: 10.1126/science.aac4255 (DOI)
Publication: 10.1126/science.aad1329 (DOI)
Publication: 10.1016/j.neo.2017.08.004 (DOI)
Publication: 10.1126/science.aan4236 (DOI)
Publication: 10.1126/science.aao3290 (DOI)
Publication: 10.1186/s13073-019-0672-4 (DOI)
Publication: 10.1126/science.aaz7015 (DOI)
Publication: 10.1038/s41591-022-01698-2 (DOI)
Publication: 10.1038/s41591-022-01695-5 (DOI)
Publication: 10.1038/s41591-022-01965-2 (DOI)
Publication: 10.1038/s41396-020-0690-7 (DOI)
Publication: 10.1038/s41591-024-02803-3 (DOI)
Publication: 10.1016/j.chom.2024.10.006 (DOI)
Publication: 10.1126/science.abb5920 (DOI)
Publication: 10.1038/s41591-023-02453-x (DOI)
Publication: 10.1136/jitc-2025-012659 (DOI)
Publication: 10.3389/fmed.2025.1673880 (DOI)
Publication: 10.1111/pcmr.13224 (DOI)
Publication: 10.1126/science.aay9189 (DOI)
Publication: 10.1016/j.ccell.2023.12.003 (DOI)
Publication: 10.1038/s41586-021-03368-8 (DOI)
Publication: 10.1016/j.cell.2021.09.019 (DOI)
Publication: 10.1126/science.abc3421 (DOI)
Publication: 10.1016/j.immuni.2019.06.002 (DOI)
Publication: 10.1038/s41467-020-16079-x (DOI)
Publication: 10.1126/science.abo2296 (DOI)

References

  • 1. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23. https://doi.org/10.1056/NEJMoa1003466
  • 2. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-65. https://doi.org/10.1056/NEJMoa1200694
  • 3. Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386:24-34. https://doi.org/10.1056/NEJMoa2109970
  • 4. Wolchok JD, Chiarion-Sileni V, Rutkowski P, Cowey CL, Schadendorf D, Wagstaff J, et al. Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2025;392:11-22. https://doi.org/10.1056/NEJMoa2407417
  • 5. Hassel JC, Zimmer L, Sickmann T, Eigentler TK, Meier F, Mohr P, et al. Medical needs and therapeutic options for melanoma patients resistant to anti-pd-1-directed immune checkpoint inhibition. Cancers (Basel). 2023;15:3448. https://doi.org/10.3390/cancers15133448
  • 6. Sznol M, Ferrucci PF, Hogg D, Atkins MB, Wolter P, Guidoboni M, et al. Pooled analysis safety profile of nivolumab and ipilimumab combination therapy in patients with advanced melanoma. J Clin Oncol. 2017;35:3815-22. https://doi.org/10.1200/JCO.2016.72.1167
  • 7. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350:1084-9. https://doi.org/10.1126/science.aac4255
  • 8. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079-84. https://doi.org/10.1126/science.aad1329
  • 9. Frankel AE, Coughlin LA, Kim J, Froehlich TW, Xie Y, Frenkel EP, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia. 2017;19:848-55. https://doi.org/10.1016/j.neo.2017.08.004
  • 10. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97-103. https://doi.org/10.1126/science.aan4236
  • 11. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104-8. https://doi.org/10.1126/science.aao3290
  • 12. Peters BA, Wilson M, Moran U, Pavlick A, Izsak A, Wechter T, et al. Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients. Genome Med. 2019;11:61. https://doi.org/10.1186/s13073-019-0672-4
  • 13. Spencer CN, McQuade JL, Gopalakrishnan V, McCulloch JA, Vetizou M, Cogdill AP, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science. 2021;374:1632-40. https://doi.org/10.1126/science.aaz7015
  • 14. McCulloch JA, Davar D, Rodrigues RR, Badger JH, Fang JR, Cole AM, et al. Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1. Nat Med. 2022;28:545-56. https://doi.org/10.1038/s41591-022-01698-2
  • 15. Lee KA, Thomas AM, Bolte LA, Björk JR, de Ruijter LK, Armanini F, et al. Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat Med. 2022;28:535-44. https://doi.org/10.1038/s41591-022-01695-5
  • 16. Simpson RC, Shanahan ER, Batten M, Reijers ILM, Read M, Silva IP, et al. Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome. Nat Med. 2022;28:2344-52. https://doi.org/10.1038/s41591-022-01965-2
  • 17. Belheouane M, Vallier M, Čepić A, Chung CJ, Ibrahim S, Baines JF. Assessing similarities and disparities in the skin microbiota between wild and laboratory populations of house mice. ISME J. 2020;14:2367-80. https://doi.org/10.1038/s41396-020-0690-7
  • 18. Björk JR, Bolte LA, Maltez Thomas A, Lee KA, Rossi N, Wind TT, et al. Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma. Nat Med. 2024;30:785-96. https://doi.org/10.1038/s41591-024-02803-3
  • 19. Macandog ADG, Catozzi C, Capone M, Nabinejad A, Nanaware PP, Liu S, et al. Longitudinal analysis of the gut microbiota during anti-PD-1 therapy reveals stable microbial features of response in melanoma patients. Cell Host Microbe. 2024;32:2004-18.e9. https://doi.org/10.1016/j.chom.2024.10.006
  • 20. Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021;371:602-9. https://doi.org/10.1126/science.abb5920
  • 21. Routy B, Lenehan JG, Miller WH, Jr., Jamal R, Messaoudene M, Daisley BA, et al. Fecal microbiota transplantation plus anti-PD-1anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. Nat Med. 2023;29:2121-32. https://doi.org/10.1038/s41591-023-02453-x
  • 22. Hadi DK, Baines KJ, Jabbarizadeh B, Miller WH, Jamal R, Ernst S, et al. Improved survival in advanced melanoma patients treated with fecal microbiota transplantation using healthy donor stool in combination with anti-PD1: final results of the MIMic phase 1 trial. J Immunother Cancer. 2025;13(8). https://doi.org/10.1136/jitc-2025-012659
  • 23. Bautista J, Villegas-Chávez JA, Bunces-Larco D, Martín-Aguilera R, López-Cortés A. The microbiome as a therapeutic co-driver in melanoma immuno-oncology. Front Med (Lausanne). 2025;12:1673880. https://doi.org/10.3389/fmed.2025.1673880
  • 24. L'Orphelin JM, Dompmartin A, Dréno B. The skin microbiome: a new key player in melanoma, from onset to metastatic stage. Pigment Cell Melanoma Res. 2025;38:e13224. https://doi.org/10.1111/pcmr.13224
  • 25. Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. 2020;368:973-80. https://doi.org/10.1126/science.aay9189
  • 26. Routy B, Jackson T, Mählmann L, Baumgartner CK, Blaser M, Byrd A, et al. Melanoma and microbiota: Current understanding and future directions. Cancer Cell. 2024;42:16-34. https://doi.org/10.1016/j.ccell.2023.12.003
  • 27. Kalaora S, Nagler A, Nejman D, Alon M, Barbolin C, Barnea E, et al. Identification of bacteria-derived HLA-bound peptides in melanoma. Nature. 2021;592:138-43. https://doi.org/10.1038/s41586-021-03368-8
  • 28. Lam KC, Araya RE, Huang A, Chen Q, Di Modica M, Rodrigues RR, et al. Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell. 2021;184:5338-56.e21. https://doi.org/10.1016/j.cell.2021.09.019
  • 29. Mager LF, Burkhard R, Pett N, Cooke NCA, Brown K, Ramay H, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science. 2020;369:1481-9. https://doi.org/10.1126/science.abc3421
  • 30. Bachem A, Makhlouf C, Binger KJ, de Souza DP, Tull D, Hochheiser K, et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8(+) T cells. Immunity. 2019;51:285-97.e5. https://doi.org/10.1016/j.immuni.2019.06.002
  • 31. Coutzac C, Jouniaux JM, Paci A, Schmidt J, Mallardo D, Seck A, et al. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat Commun. 2020;11:2168. https://doi.org/10.1038/s41467-020-16079-x
  • 32. Fidelle M, Rauber C, Alves Costa Silva C, Tian AL, Lahmar I, de La Varende AM, et al. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers. Science. 2023;380:eabo2296. https://doi.org/10.1126/science.abo2296