{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:01:16Z","timestamp":1790208076446,"version":"4.1.0"},"reference-count":80,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["72274192"],"award-info":[{"award-number":["72274192"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["WIREs Mechanisms of Disease"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The immune\u2010oncology\u2010microbiome (IOM) trio highlights the significant role of microbiomes in cancer progression by modulating immune evasion, genomic instability, and inflammation\u2014key hallmarks of cancer. While microbiomes can exert both protective and detrimental effects on tumor development and treatment response, the mechanistic underpinnings\u2014particularly those involving intratumoral microbiomes\u2014remain poorly understood. To elucidate these dynamics, we frame the interplay between cancer, immune cells, and microbiomes through the lens of the Anna Karenina Principle (AKP)\u2014using Leo Tolstoy's aphorism: \u201cAll happy families are alike; each unhappy family is unhappy in its own way.\u201d In biomedical terms, this translates to: all healthy systems including intratumoral microbiomes are alike, but each dysfunctional system fails in its own way. We hypothesize that either AKP or its inverse (anti\u2010AKP) may govern microbial interactions that influence cancer progression. Analyzing four published cancer tissue microbiome datasets (Nejman 2020, Science), we identified two distinct patterns: AKP\u2010driven increased microbial heterogeneity in lung and ovarian cancers, and anti\u2010AKP\u2010driven decreased heterogeneity in breast and colon cancers. We further propose cancer microbiome therapy (CMT) as an emerging frontier in microbiome\u2010based therapeutics. The CMT may include the following strategies: (i) Restoring a healthy microbiome (including barrier tissue, tumor, blood microbiomes) to enhance immune function through ecosystem engineering; (ii) Developing specific microbial agents (species or their metabolites) to modulate crossroads of cancer immunotherapy; (iii) Engineering microbial agents to suppress cancer\u2010causing microbes (oncomicrobes and complicit) and halt cancer progression; (iv) Reviving historical approaches like Coley's toxin and oncolytic viruses for direct cancer cell targeting.<\/jats:p>\n                  <jats:p>\n                    This article is categorized under:\n                    <jats:list list-type=\"simple\">\n                      <jats:list-item>\n                        <jats:p>Cancer &gt; Genetics\/Genomics\/Epigenetics<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Cancer &gt; Computational Models<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>","DOI":"10.1002\/wsbm.70004","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T14:08:17Z","timestamp":1763129297000},"source":"Crossref","is-referenced-by-count":7,"title":["Anna Karenina Principle, Immune\u2010Oncology\u2010Microbiome Trio and Cancer Microbiome Therapy"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4397-2630","authenticated-orcid":false,"given":"Zhanshan (Sam)","family":"Ma","sequence":"first","affiliation":[{"name":"Faculty of Arts and Sciences Harvard University  Cambridge Massachusetts USA"},{"name":"Computational Biology and Medical Ecology Lab, Biostatistics and Image Genetics Lab Kunming Institute of Zoology, Chinese Academy of Sciences  Kunming China"},{"name":"Microbiome Medicine and Advanced AI Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-025-03787-x"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1608-2"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2020.01.019"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010018\u20100014\u2010x"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.255620.119"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abc4552"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.1551"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2024.12.005"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1890\/11-1817.1"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-ecolsys-120213-091540"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010022\u201000547\u20103"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah3648"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/eva.13190"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-025-01211-7"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1890\/09-1692.1"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13027"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah5043"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.17049"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2017.00096"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0174"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1059"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan1295"},{"key":"e_1_2_11_25_1","volume-title":"The Ecological Theater and the Evolutionary Play","author":"Hutchinson G. 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