{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:04:35Z","timestamp":1790229875700,"version":"4.1.0"},"reference-count":140,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, but responses vary substantially among patients. Clinical studies have associated features of the gut microbiome with ICI outcomes, while experimental evidence suggests that microbial metabolites and nitric oxide (NO)-related pathways may influence antitumor immunity and tumor vascular biology. This qualitative systematic review evaluated the evidence supporting a proposed microbiome\u2013NO\u2013ICI framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Five databases were searched for peer-reviewed studies published between January 2000 and August 2025. Fifty-four distinct primary studies met the eligibility criteria, comprising 21 clinical studies, 19 animal studies and 14\n                      <jats:italic>in vitro<\/jats:italic>\n                      mechanistic studies. Evidence was synthesized narratively according to study type and thematic domain.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Several clinical cohorts associated enrichment of\n                      <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                      ,\n                      <jats:italic>Faecalibacterium prausnitzii<\/jats:italic>\n                      ,\n                      <jats:italic>Bifidobacterium<\/jats:italic>\n                      species and other short-chain fatty acid\u2013producing taxa with favorable ICI outcomes; however, the reported microbial signatures varied across cohorts and analytical platforms. Microbial-transfer experiments and early non-randomized fecal microbiota transplantation studies provide proof-of-concept evidence that microbiome composition can influence antitumor immune responses, although the clinical intervention evidence remains preliminary. Animal and cellular studies indicate that microbial metabolites, host nitric oxide synthase pathways and reactive nitrogen signaling can affect immune-cell function, vascular regulation and tumor hypoxia. Direct clinical evidence linking microbiota-mediated nitrate reduction or dietary nitrate supplementation to improved ICI outcomes is lacking. Human dietary nitrate studies conducted outside oncology demonstrate increased circulating nitrate and nitrite and measurable vascular effects but do not establish anticancer or ICI efficacy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The microbiome\u2013NO\u2013ICI axis should be regarded as a testable integrative model linking microbial ecology, immune regulation and tumor vascular biology. Current evidence supports biological plausibility but is insufficient to establish NO- or microbiome-directed interventions as effective adjuncts to ICI therapy. Prospective mechanistic studies and biomarker-driven clinical trials are required before therapeutic translation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1904698","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:44:05Z","timestamp":1790228645000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The microbiome\u2013nitric oxide axis in cancer immunotherapy: a targeted qualitative systematic review of mechanistic and translational evidence"],"prefix":"10.3389","volume":"17","author":[{"given":"Michael","family":"Enwere","sequence":"first","affiliation":[{"name":"Global Health Equity Foundation (GHEF)","place":["Bear, DE, United States"]},{"name":"PrimeLife360 Wellness","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan S.","family":"Bryan","sequence":"additional","affiliation":[{"name":"Bryan 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