{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:44:06Z","timestamp":1791233046434,"version":"4.1.0"},"reference-count":118,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shenzhen Medical Research Fund","award":["C2301001"],"award-info":[{"award-number":["C2301001"]}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2023YFC3503200"],"award-info":[{"award-number":["2023YFC3503200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2023YFC3503205"],"award-info":[{"award-number":["2023YFC3503205"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>The intratumoral microbiota has emerged as a critical component of the tumor microenvironment (TME), with accumulating evidence indicating that its biological functions are influenced not only by microbial composition but also by their spatial organization within tumor tissues. This review summarizes the historical development and potential origins of intratumoral microbiota, and elaborates on the concept and biological significance of spatial heterogeneity. Based on recurrent spatial distribution patterns reported across different tumor types, we propose a conceptual framework comprising several putative spatial niches, including hypoxic\/necrotic, immune-enriched, stromal-associated, invasive\/metastatic, and intracellular niches. We further discuss the potential mechanisms contributing to the establishment and maintenance of spatial heterogeneity. The clinical significance of spatial microbial signatures is critically evaluated, alongside a comprehensive overview of spatial analytical methodologies, ranging from in situ hybridization and immunology-based approaches to emerging spatial omics and multi-omics integration strategies. Finally, we address key challenges and limitations, including contamination control, causal inference, barriers to clinical translation, and the underexplored spatial dimensions of the intratumoral mycobiome and virome. By synthesizing current knowledge and identifying critical gaps, this review aims to provide a conceptual and methodological framework for advancing spatially resolved investigations of intratumoral microbiota and facilitating their potential translational applications in precision oncology.<\/jats:p>","DOI":"10.3390\/pathogens15070687","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:58:04Z","timestamp":1782799084000},"page":"687","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Spatial Heterogeneity of Intratumoral Microbiota and Its Roles in Tumor\u2013Microbiota Interactions and Therapeutic Implications"],"prefix":"10.3390","volume":"15","author":[{"given":"Li","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Molecular Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongzhen","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinan","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjiaxi","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5586-4055","authenticated-orcid":false,"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"},{"name":"Laboratory Animal Center, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ccell.2023.02.016","article-title":"The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth","volume":"41","author":"Joyce","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1126\/science.aay9189","article-title":"The human tumor microbiome is composed of tumor type-specific intracellular bacteria","volume":"368","author":"Nejman","year":"2020","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Salter, S.J., Cox, M.J., Turek, E.M., Calus, S.T., Cookson, W.O., Moffatt, M.F., Turner, P., Parkhill, J., Loman, N.J., and Walker, A.W. (2014). Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol., 12.","DOI":"10.1186\/s12915-014-0087-z"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.tim.2018.11.003","article-title":"Contamination in Low Microbial Biomass Microbiome Studies: Issues and Recommendations","volume":"27","author":"Eisenhofer","year":"2019","journal-title":"Trends Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.chom.2020.12.001","article-title":"The cancer microbiome atlas: A pan-cancer comparative analysis to distinguish tissue-resident microbiota from contaminants","volume":"29","author":"Dohlman","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1001\/jamaoncol.2022.2810","article-title":"Association of Intratumoral Microbiota with Prognosis in Patients with Nasopharyngeal Carcinoma from 2 Hospitals in China","volume":"8","author":"Qiao","year":"2022","journal-title":"JAMA Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"eadu1727","DOI":"10.1126\/sciadv.adu1727","article-title":"Intratumoral mycobiome heterogeneity influences the tumor microenvironment and immunotherapy outcomes in renal cell carcinoma","volume":"11","author":"Mou","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/s41586-022-05435-0","article-title":"Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer","volume":"611","author":"Wu","year":"2022","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1016\/j.ccell.2023.08.012","article-title":"The intratumor mycobiome promotes lung cancer progression via myeloid-derived suppressor cells","volume":"41","author":"Liu","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s40168-024-01907-9","article-title":"Tumor-colonized Streptococcus mutans metabolically reprograms tumor microenvironment and promotes oral squamous cell carcinoma","volume":"12","author":"Zhou","year":"2024","journal-title":"Microbiome"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.chom.2013.07.007","article-title":"Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment","volume":"14","author":"Kostic","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1101\/gr.126516.111","article-title":"Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma","volume":"22","author":"Castellarin","year":"2012","journal-title":"Genome Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1126\/science.aah5043","article-title":"Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine","volume":"357","author":"Geller","year":"2017","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1038\/s41467-018-03900-x","article-title":"Multi-faceted immunomodulatory and tissue-tropic clinical bacterial isolate potentiates prostate cancer immunotherapy","volume":"9","author":"Anker","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1073\/pnas.1614315114","article-title":"Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors","volume":"114","author":"Xin","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1152\/physiolgenomics.00103.2023","article-title":"Host-microbiota interactions contributing to the heterogeneous tumor microenvironment in colorectal cancer","volume":"56","author":"Li","year":"2024","journal-title":"Physiol. Genom."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1158\/2159-8290.CD-17-1134","article-title":"The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression","volume":"8","author":"Pushalkar","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Irfan, M., Delgado, R.Z.R., and Frias-Lopez, J. (2020). The Oral Microbiome and Cancer. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.591088"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.trecan.2021.01.010","article-title":"Gut Microbiota in Cancer Immune Response and Immunotherapy","volume":"7","author":"Zhou","year":"2021","journal-title":"Trends Cancer"},{"key":"ref_20","first-page":"303","article-title":"Impact of the Gastrointestinal Microbiome in Health and Disease: Co-evolution with the Host Immune System","volume":"421","author":"Hold","year":"2019","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.semcancer.2021.07.005","article-title":"Microbiome dysbiosis and epigenetic modulations in lung cancer: From pathogenesis to therapy","volume":"86","author":"Khan","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"102431","DOI":"10.1016\/j.xcrm.2025.102431","article-title":"The comprehensive oral microbiome landscape unveils its interplay with poor oral health in esophageal squamous cell carcinoma risk","volume":"6","author":"Gao","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.ccell.2021.03.004","article-title":"Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver","volume":"39","author":"Bertocchi","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s10020-021-00295-2","article-title":"The role of the microbiome in ovarian cancer: Mechanistic insights into oncobiosis and to bacterial metabolite signaling","volume":"27","author":"Sipos","year":"2021","journal-title":"Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1136\/gutjnl-2023-330941","article-title":"Oral bacteria accelerate pancreatic cancer development in mice","volume":"73","author":"Saba","year":"2024","journal-title":"Gut"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2073785","DOI":"10.1080\/19490976.2022.2073785","article-title":"Periodontitis pathogen Porphyromonas gingivalis promotes pancreatic tumorigenesis via neutrophil elastase from tumor-associated neutrophils","volume":"14","author":"Tan","year":"2022","journal-title":"Gut Microbes"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41368-024-00342-8","article-title":"Porphyromonas gingivalis potentiates stem-like properties of oral squamous cell carcinoma by modulating SCD1-dependent lipid synthesis via NOD1\/KLF5 axis","volume":"17","author":"Zang","year":"2025","journal-title":"Int. J. Oral Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Pignatelli, P., Nuccio, F., Piattelli, A., and Curia, M.C. (2023). The Role of Fusobacterium nucleatum in Oral and Colorectal Carcinogenesis. Microorganisms, 11.","DOI":"10.3390\/microorganisms11092358"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1016\/j.cell.2022.02.027","article-title":"Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer","volume":"185","author":"Fu","year":"2022","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e70070","DOI":"10.1002\/imt2.70070","article-title":"The microbiome in cancer","volume":"4","author":"Lin","year":"2025","journal-title":"iMeta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e0008924","DOI":"10.1128\/msystems.00089-24","article-title":"Distinct oral-associated gastric microbiota and Helicobacter pylori communities for spatial microbial heterogeneity in gastric cancer","volume":"9","author":"Lei","year":"2024","journal-title":"mSystems"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1038\/s41591-025-03957-4","article-title":"Microbial signals in primary and metastatic brain tumors","volume":"31","author":"Morad","year":"2025","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1016\/j.cell.2024.03.021","article-title":"A pan-cancer analysis of the microbiome in metastatic cancer","volume":"187","author":"Battaglia","year":"2024","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101397","DOI":"10.1016\/j.xcrm.2024.101397","article-title":"Multimodal immune phenotyping reveals microbial-T cell interactions that shape pancreatic cancer","volume":"5","author":"Li","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/s41392-025-02335-3","article-title":"Microbiota in cancer: Current understandings and future perspectives","volume":"11","author":"Yao","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ccell.2025.12.009","article-title":"Spatial omics at the forefront: Emerging technologies, analytical innovations, and clinical applications","volume":"44","author":"Liu","year":"2026","journal-title":"Cancer Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.ccell.2025.09.010","article-title":"Tumor-infiltrating bacteria disrupt cancer epithelial cell interactions and induce cell-cycle arrest","volume":"44","author":"Ponath","year":"2026","journal-title":"Cancer Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1016\/j.cell.2025.12.044","article-title":"Divergent tumor immunity determined by bacteria-cancer cell engagement","volume":"189","author":"Yao","year":"2026","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"102820","DOI":"10.1016\/j.arr.2025.102820","article-title":"The role of intratumoral microbiome in the occurrence, proliferation, metastasis of colorectal cancer and its underlying therapeutic strategies","volume":"111","author":"Liao","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/s41392-023-01332-8","article-title":"Hypoxic microenvironment in cancer: Molecular mechanisms and therapeutic interventions","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.jconrel.2014.12.014","article-title":"Trg-deficient Salmonella colonize quiescent tumor regions by exclusively penetrating or proliferating","volume":"199","author":"Zhang","year":"2015","journal-title":"J. Control. Release Off. J. Control. Release Soc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"217964","DOI":"10.1016\/j.canlet.2025.217964","article-title":"Bacteria and tumor debris induced pancreatic cancer progression via the NF-\u03baB signaling pathway","volume":"632","author":"Chen","year":"2025","journal-title":"Cancer Lett."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lavin, R.C., and Tan, S. (2022). Spatial relationships of intra-lesion heterogeneity in Mycobacterium tuberculosis microenvironment, replication status, and drug efficacy. PLoS Pathog., 18.","DOI":"10.1371\/journal.ppat.1010459"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2156255","DOI":"10.1080\/19490976.2022.2156255","article-title":"Intratumor microbiome features reveal antitumor potentials of intrahepatic cholangiocarcinoma","volume":"15","author":"Chai","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5338","DOI":"10.1016\/j.cell.2021.09.019","article-title":"Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment","volume":"184","author":"Lam","year":"2021","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ccell.2022.01.003","article-title":"Fungal mycobiome drives IL-33 secretion and type 2 immunity in pancreatic cancer","volume":"40","author":"Alam","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/s43018-025-01067-1","article-title":"Intratumoral bacteria are immunosuppressive and promote immunotherapy resistance in head and neck squamous cell carcinoma","volume":"7","author":"Silver","year":"2026","journal-title":"Nat. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41392-024-01979-x","article-title":"Cold and hot tumors: From molecular mechanisms to targeted therapy","volume":"9","author":"Wu","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1158\/0008-5472.CAN-24-2580","article-title":"Intratumoral Fusobacterium nucleatum Recruits Tumor-Associated Neutrophils to Promote Gastric Cancer Progression and Immune Evasion","volume":"85","author":"Zhang","year":"2025","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1158\/2159-8290.CD-24-1259","article-title":"Intrahepatic Microbial Heterogeneity in Multifocal Hepatocellular Carcinoma and Its Association with Host Genomic and Transcriptomic Alterations","volume":"15","author":"Lu","year":"2025","journal-title":"Cancer Discov."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2560695","DOI":"10.1080\/19490976.2025.2560695","article-title":"The intratumoral microbiota in breast cancer: From basic research to clinical translation","volume":"17","author":"Xu","year":"2025","journal-title":"Gut Microbes"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e70273","DOI":"10.1002\/ctm2.70273","article-title":"Integrated spatial multi-omics profiling of Fusobacterium nucleatum in breast cancer unveils its role in tumour microenvironment modulation and cancer progression","volume":"15","author":"Zhao","year":"2025","journal-title":"Clin. Transl. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1111\/jgh.15361","article-title":"Heterogeneous distribution of Fusobacterium nucleatum in the progression of colorectal cancer","volume":"36","author":"Yamamoto","year":"2021","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3666","DOI":"10.1111\/cas.15901","article-title":"Intratumor Fusobacterium nucleatum promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis","volume":"114","author":"Hayashi","year":"2023","journal-title":"Cancer Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e0387324","DOI":"10.1128\/mbio.03873-24","article-title":"Tumor-colonizing Pseudoalteromonas elyakovii metabolically reprograms the tumor microenvironment and promotes breast ductal carcinoma","volume":"16","author":"Liu","year":"2025","journal-title":"mBio"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"0002","DOI":"10.34133\/cancomm.0002","article-title":"The Spatiotemporal Heterogeneity of Tumor-Associated Stromal Cells: Reprogramming Plasticity to Unlock Precision Cancer Immunotherapy","volume":"46","author":"Lv","year":"2026","journal-title":"Cancer Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1016\/j.ccell.2024.08.011","article-title":"Classifying cancer-associated fibroblasts-The good, the bad, and the target","volume":"42","author":"Cords","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5375","DOI":"10.1038\/s44318-025-00542-w","article-title":"Fusobacterium nucleatum interacts with cancer-associated fibroblasts to promote colorectal cancer","volume":"44","author":"Karta","year":"2025","journal-title":"EMBO J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1002\/ags3.70116","article-title":"Intratumoral Fusobacterium nucleatum Drives Cancer-Associated Fibroblasts Enrichment and Immune Exclusion in Esophageal Squamous Cell Carcinoma","volume":"10","author":"Ofuchi","year":"2026","journal-title":"Ann. Gastroenterol. Surg."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e004698","DOI":"10.1136\/jitc-2022-004698","article-title":"Spatial meta-transcriptomics reveal associations of intratumor bacteria burden with lung cancer cells showing a distinct oncogenic signature","volume":"10","author":"Dong","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Wang, M., Yu, F., and Li, P. (2023). Intratumor microbiota in cancer pathogenesis and immunity: From mechanisms of action to therapeutic opportunities. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1269054"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"217913","DOI":"10.1016\/j.canlet.2025.217913","article-title":"Hypoxia and immunometabolism in the tumor microenvironment: Insights into mechanisms and therapeutic potential","volume":"631","author":"Wu","year":"2025","journal-title":"Cancer Lett."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Walker, S.P., Tangney, M., and Claesson, M.J. (2020). Sequence-Based Characterization of Intratumoral Bacteria\u2014A Guide to Best Practice. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00179"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1038\/s41598-022-05554-8","article-title":"pH-taxis drives aerobic bacteria in duodenum to migrate into the pancreas with tumors","volume":"12","author":"Shirai","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.chom.2016.07.006","article-title":"Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc","volume":"20","author":"Abed","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1001\/jamaoncol.2015.1377","article-title":"Fusobacterium nucleatum and T Cells in Colorectal Carcinoma","volume":"1","author":"Mima","year":"2015","journal-title":"JAMA Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3789","DOI":"10.1016\/j.cell.2022.09.005","article-title":"Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions","volume":"185","author":"Livyatan","year":"2022","journal-title":"Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e00023","DOI":"10.1002\/adbi.202500023","article-title":"Bacterial Quorum Sensing: A Double-Edged Sword in Cancer Development","volume":"9","author":"Paniz","year":"2025","journal-title":"Adv. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"105708","DOI":"10.1016\/j.ebiom.2025.105708","article-title":"The metabolic dialogue between intratumoural microbes and cancer: Implications for immunotherapy","volume":"115","author":"Situ","year":"2025","journal-title":"eBioMedicine"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s40168-026-02378-w","article-title":"The interplay between Peptostreptococcus and Fusobacterium as novel signatures in colorectal cancer recurrence","volume":"14","author":"Zhang","year":"2026","journal-title":"Microbiome"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"116473","DOI":"10.1016\/j.celrep.2025.116473","article-title":"PreTA-mediated metabolism of 5-fluorouracil by intratumoral Citrobacter freundii drives chemoresistance in pancreatic cancer","volume":"44","author":"Xu","year":"2025","journal-title":"Cell Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e2301679","DOI":"10.1002\/advs.202301679","article-title":"Discovery of Intratumoral Oncolytic Bacteria Toward Targeted Anticancer Theranostics","volume":"10","author":"Goto","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.immuni.2018.06.006","article-title":"Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy","volume":"49","author":"Li","year":"2018","journal-title":"Immunity"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"20242282","DOI":"10.1084\/jem.20242282","article-title":"Tumor cell heterogeneity drives spatial organization of the intratumoral immune response","volume":"222","author":"Tanaka","year":"2025","journal-title":"J. Exp. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e1331","DOI":"10.1002\/ctm2.1331","article-title":"Intratumoural microbiome can predict the prognosis of hepatocellular carcinoma after surgery","volume":"13","author":"Sun","year":"2023","journal-title":"Clin. Transl. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1158\/0008-5472.CAN-25-3400","article-title":"Intratumoral P. copri Reprograms MARCO+ Tumor-Associated Macrophages by Depleting Glycerophosphocholine to Drive Colorectal Cancer Progression","volume":"86","author":"Yuan","year":"2026","journal-title":"Cancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1186\/s12951-022-01373-1","article-title":"Bacteria-driven hypoxia targeting delivery of chemotherapeutic drug proving outcome of breast cancer","volume":"20","author":"Xiao","year":"2022","journal-title":"J. Nanobiotechnol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Xu, S., Zhang, T., Song, Y., Wang, M., Wu, R., Li, M., Wang, H., Xie, X., Chen, Q., and Ma, X. (2026). Sustained nitric oxide production by engineered E. coli remodels the tumor microenvironment and potentiates immunotherapy. Nat. Biotechnol.","DOI":"10.1038\/s41587-026-03054-y"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.chom.2026.02.010","article-title":"Leveraging intratumoral probiotics for pancreatic cancer immunotherapy via xenophagy","volume":"34","author":"Li","year":"2026","journal-title":"Cell Host Microbe"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e06486","DOI":"10.1002\/advs.202406486","article-title":"Self-Adjusting Engineered Probiotic for Targeted Tumor Colonization and Local Therapeutics Delivery","volume":"12","author":"Zou","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e07820","DOI":"10.1002\/advs.202507820","article-title":"Engineering Bacteria as Living Therapeutics in Cancer Therapy","volume":"12","author":"Chen","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Ragothaman, M., and Yoo, S.Y. (2023). Engineered Phage-Based Cancer Vaccines: Current Advances and Future Directions. Vaccines, 11.","DOI":"10.3390\/vaccines11050919"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"7892","DOI":"10.1039\/D3NR05082C","article-title":"Self-propelling bacteria-based magnetic nanoparticles (BacMags) for targeted magnetic hyperthermia therapy against hypoxic tumors","volume":"16","author":"Kaur","year":"2024","journal-title":"Nanoscale"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"189355","DOI":"10.1016\/j.bbcan.2025.189355","article-title":"Decoding the role of intratumoral microbiota in gastric cancer","volume":"1880","author":"Gui","year":"2025","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Gu, J., Wang, H., Zhang, M., Xiong, Y., Yang, L., Ren, B., and Huang, R. (2022). Application of Fluorescence In Situ Hybridization (FISH) in Oral Microbial Detection. Pathogens, 11.","DOI":"10.3390\/pathogens11121450"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12967-025-07543-7","article-title":"Intratumoral Collinsella aerofaciens exhibits antitumor activity in endometrial carcinoma through activation of the p53 signaling pathway","volume":"24","author":"Tao","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e0098322","DOI":"10.1128\/spectrum.00983-22","article-title":"The Intratumoral Bacterial Metataxonomic Signature of Hepatocellular Carcinoma","volume":"10","author":"Huang","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jmoldx.2011.08.002","article-title":"RNAscope: A novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues","volume":"14","author":"Wang","year":"2012","journal-title":"J. Mol. Diagn. JMD"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.1158\/0008-5472.CAN-22-2593","article-title":"Intratumoral Microbiota Composition Regulates Chemoimmunotherapy Response in Esophageal Squamous Cell Carcinoma","volume":"83","author":"Wu","year":"2023","journal-title":"Cancer Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e202100351","DOI":"10.1002\/jbio.202100351","article-title":"Comprehensive histological imaging of native microbiota in human glioma","volume":"15","author":"Zhao","year":"2022","journal-title":"J. Biophotonics"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nbt.1868","article-title":"PathSeq: Software to identify or discover microbes by deep sequencing of human tissue","volume":"29","author":"Kostic","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.1093\/bioinformatics\/bty501","article-title":"GATK PathSeq: A customizable computational tool for the discovery and identification of microbial sequences in libraries from eukaryotic hosts","volume":"34","author":"Walker","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3817","DOI":"10.1016\/j.cell.2026.04.015","article-title":"Biodiversity and biogeography of the multi-kingdom cancer microbiome","volume":"189","author":"Dohlman","year":"2026","journal-title":"Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6554","DOI":"10.1016\/j.cell.2025.08.008","article-title":"Stereo-seq V2: Spatial mapping of total RNA on FFPE sections with high resolution","volume":"188","author":"Zhao","year":"2025","journal-title":"Cell"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1038\/s41587-023-01988-1","article-title":"Spatial host-microbiome sequencing reveals niches in the mouse gut","volume":"42","author":"Xavier","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"eadr0932","DOI":"10.1126\/science.adr0932","article-title":"Highly multiplexed spatial transcriptomics in bacteria","volume":"387","author":"Sarfatis","year":"2025","journal-title":"Science"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2320291","DOI":"10.1080\/19490976.2024.2320291","article-title":"The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance","volume":"16","author":"Dalmasso","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Yiu, S.P.T., Chang, Y., Yeo, Y.Y., Qiu, H., Wu, W., Michel, H.A., Jin, X., Huang, R., Kure, S., and Parmelee, L. (2026). Same-Slide Spatial Multi-Omics Integration with IN-DEPTH Reveals Tumor Virus-Linked Spatial Reorganization of the Tumor Microenvironment. Cancer Discov., OF1\u2013OF38.","DOI":"10.1158\/2159-8290.CD-25-0775"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Wang, Z., Zhang, T., and Liu, Y. (2025). Emerging technologies and current challenges in intratumoral microbiota research. Front. Cell. Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1685862"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1111\/1755-0998.13011","article-title":"Laboratory contamination over time during low-biomass sample analysis","volume":"19","author":"Weyrich","year":"2019","journal-title":"Mol. Ecol. Resour."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/s41564-025-02035-2","article-title":"Guidelines for preventing and reporting contamination in low-biomass microbiome studies","volume":"10","author":"Fierer","year":"2025","journal-title":"Nat. Microbiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1186\/s40168-018-0605-2","article-title":"Simple statistical identification and removal of contaminant sequences in marker-gene and metagenomics data","volume":"6","author":"Davis","year":"2018","journal-title":"Microbiome"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/edn3.11","article-title":"microDecon: A highly accurate read-subtraction tool for the post-sequencing removal of contamination in metabarcoding studies","volume":"1","author":"McKnight","year":"2019","journal-title":"Environ. DNA"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/nmeth.1650","article-title":"Bayesian community-wide culture-independent microbial source tracking","volume":"8","author":"Knights","year":"2011","journal-title":"Nat. Methods"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"6799","DOI":"10.1038\/s41467-022-34409-z","article-title":"De novo identification of microbial contaminants in low microbial biomass microbiomes with Squeegee","volume":"13","author":"Liu","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1038\/s41587-023-01696-w","article-title":"Contamination source modeling with SCRuB improves cancer phenotype prediction from microbiome data","volume":"41","author":"Austin","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1126\/science.aal5240","article-title":"Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer","volume":"358","author":"Bullman","year":"2017","journal-title":"Science"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"eaba1590","DOI":"10.1126\/sciadv.aba1590","article-title":"Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer","volume":"6","author":"Dong","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3259","DOI":"10.1038\/s41467-020-16967-2","article-title":"Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression","volume":"11","author":"Parhi","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1126\/science.aah3648","article-title":"Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria","volume":"359","author":"Dejea","year":"2018","journal-title":"Science"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1038\/nbt.3981","article-title":"Assessment of variation in microbial community amplicon sequencing by the Microbiome Quality Control (MBQC) project consortium","volume":"35","author":"Sinha","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Plummer, J.T., Dezem, F.S., Cook, D.P., Park, J., Zhang, L., Liu, Y., Mar\u00e7\u00e3o, M., DuBose, H., Wani, A., and Wise, K. (2025). Standardized metrics for assessment and reproducibility of imaging-based spatial transcriptomics datasets. Nat. Biotechnol., 1\u201313.","DOI":"10.1038\/s41587-025-02811-9"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"105608","DOI":"10.1016\/j.ebiom.2025.105608","article-title":"Intraneoplastic fungal dysbiosis is associated with colorectal cancer progression and host gene mutation","volume":"113","author":"Yuan","year":"2025","journal-title":"eBioMedicine"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s43046-026-00370-x","article-title":"The non-bacterial oncobiome: The role of the mycobiome and virome in tumor plasticity","volume":"38","author":"Ajeh","year":"2026","journal-title":"J. Egypt. Natl. Cancer Inst."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.trecan.2024.02.009","article-title":"Into the era of mycobiome-driven cancer research","volume":"10","author":"Liu","year":"2024","journal-title":"Trends Cancer"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"101231","DOI":"10.1016\/j.coviro.2022.101231","article-title":"Emerging technologies in the study of the virome","volume":"54","author":"Smith","year":"2022","journal-title":"Curr. Opin. Virol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s12943-025-02227-8","article-title":"The mycobiome in human cancer: Analytical challenges, molecular mechanisms, and therapeutic implications","volume":"24","author":"Ding","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.1002\/imt2.73","article-title":"Applying multi-omics toward tumor microbiome research","volume":"2","author":"Zhang","year":"2023","journal-title":"iMeta"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/7\/687\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T04:42:48Z","timestamp":1782967368000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/7\/687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":118,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["pathogens15070687"],"URL":"https:\/\/doi.org\/10.3390\/pathogens15070687","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}