Beyond the Gut: The intratumoral microbiome’s influence on tumorigenesis and treatment response

Abstract

The intratumoral microbiome (TM) refers to the microorganisms in the tumor tissues, including bacteria, fungi, viruses, and so on, and is distinct from the gut microbiome and circulating microbiota. TM is strongly associated with tumorigenesis, progression, metastasis, and response to therapy. This paper highlights the current status of TM. Tract sources, adjacent normal tissue, circulatory system, and concomitant tumor co-metastasis are the main origin of TM. The advanced techniques in TM analysis are comprehensively summarized. Besides, TM is involved in tumor progression through several mechanisms, including DNA damage, activation of oncogenic signaling pathways (phosphoinositide 3-kinase [PI3K], signal transducer and activator of transcription [STAT], WNT/β-catenin, and extracellular regulated protein kinases [ERK]), influence of cytokines and induce inflammatory responses, and interaction with the tumor microenvironment (anti-tumor immunity, pro-tumor immunity, and microbial-derived metabolites). Moreover, promising directions of TM in tumor therapy include immunotherapy, chemotherapy, radiotherapy, the application of probiotics/prebiotics/synbiotics, fecal microbiome transplantation, engineered microbiota, phage therapy, and oncolytic virus therapy. The inherent challenges of clinical application are also summarized. This review provides a comprehensive landscape for analyzing TM, especially the TM-related mechanisms and TM-based treatment in cancer.

Keywords

analysis methods / immunotherapy / intratumoral microbiome / treatment application / tumorpromotive and tumor-suppressive mechanisms

References

[1] 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(6494): 973–980.

[2] Lemmon MJ, van Zijl P, Fox ME, Mauchline ML, Giaccia AJ, Minton NP, et al. Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment. Gene Ther. 1997; 4(8): 791–796.

[3] Yazawa K, Fujimori M, Amano J, Kano Y, Taniguchi S. Bifidobacterium longum as a delivery system for cancer gene therapy: selective localization and growth in hypoxic tumors. Cancer Gene Ther. 2000; 7(2): 269–274.

[4] Alexeev EE, Lanis JM, Kao DJ, Campbell EL, Kelly CJ, Battista KD, et al. Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor. Am J Pathol. 2018; 188(5): 1183–1194.

[5] Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009; 15(2): 103–113.

[6] Sender R, Fuchs S, Milo R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biol. 2016; 14(8): e1002533.

[7] Cullin N, Antunes CA, Straussman R, Stein-Thoeringer CK. Elinav E. Microbiome and cancer. Cancer Cell. 2021; 39(10): 1317–1341.

[8] Yuan L, Yang P, Wei G, Hu X, Chen S, Lu J, et al. Tumor microbiome diversity influences papillary thyroid cancer invasion. Commun Biol. 2022; 5(1): 864.

[9] Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science. 2021; 371(6536): eabc4552.

[10] Galeano Nino JL, Wu H, LaCourse KD, Kempchinsky AG, Baryiames A, Barber B, et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature. 2022; 611(7937): 810–817.

[11] Irfan M, Delgado RZR, Frias-Lopez J. The Oral Microbiome and Cancer. Front Immunol. 2020; 11: 591088.

[12] Knippel RJ, Drewes JL, Sears CL. The Cancer Microbiome: Recent Highlights and Knowledge Gaps. Cancer Discov. 2021; 11(10): 2378–2395.

[13] Matson V, Chervin CS, Gajewski TF. Cancer and the Microbiome-Influence of the Commensal Microbiota on Cancer, Immune Responses, and Immunotherapy. Gastroenterology. 2021; 160(2): 600–613.

[14] Pushalkar S, Hundeyin M, Daley D, Zambirinis CP, Kurz E, Mishra A, et al. The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Cancer Discov. 2018; 8(4): 403–416.

[15] Geller LT, Barzily-Rokni M. Danino T, Jonas OH, Shental N, Nejman D, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017; 357(6356): 1156–1160.

[16] Picardo SL, Coburn B, Hansen AR. The microbiome and cancer for clinicians. Crit Rev Oncol Hematol. 2019; 141: 1–12.

[17] Yang L, Li A, Wang Y, Zhang Y. Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy. Signal Transduct Target Ther. 2023; 8(1): 35.

[18] Chen A, Neuwirth I, Herndler-Brandstetter D. Modeling the Tumor Microenvironment and Cancer Immunotherapy in Next-Generation Humanized Mice. Cancers (Basel). 2023; 15(11): 2989.

[19] Zhao W, Dai S, Yue L, Xu F, Gu J, Dai X, et al. Emerging mechanisms progress of colorectal cancer liver metastasis. Front Endocrinol (Lausanne). 2022; 13: 1081585.

[20] Ma PJ, Wang MM, Wang Y. Gut microbiota: A new insight into lung diseases. Biomed Pharmacother. 2022; 155: 113810.

[21] Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol. 2017; 17(4): 219–232.

[22] Pereira MS, Kriegel MA. Translocating Lactobacillus torments tumors via tryptophan catabolism. Cell. 2023; 167(6): 1481–1494 e18.

[23] Bender MJ, McPherson AC, Phelps CM, Pandey SP, Laughlin CR, Shapira JH, et al. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Cell. 2023; 186(9): 1846–1862 e26.

[24] Bullman S, Pedamallu CS, Sicinska E, Clancy TE, Zhang X, Cai D, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science. 2017; 358(6369): 1443–1448.

[25] Chassaing B, Kumar M, Baker MT, Singh V, Vijay-Kumar M. Mammalian gut immunity. Biomed J. 2014; 37(5): 246–258.

[26] Wei X, Chen Y, Jiang X, Peng M, Liu Y, Mo Y, et al. Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments. Mol Cancer. 2021; 20(1): 7.

[27] Fletcher AA, Kelly MS, Eckhoff AM, Allen PJ. Revisiting the intrinsic mycobiome in pancreatic cancer. Nature. 2023; 620(7972): E1–E6.

[28] Patel JB. 16S rRNA gene sequencing for bacterial pathogen identification in the clinical laboratory. Mol Diagn. 2001; 6(4): 313–321.

[29] Yarza P, Yilmaz P, Pruesse E, Glöckner FO, Ludwig W, Schleifer KH, et al. Uniting the classification of cultured and uncultured bacteria and archaea using 16S rRNA gene sequences. Nat Rev Microbiol. 2014; 12(9): 635–645.

[30] Johnson JS, Spakowicz DJ, Hong BY, Petersen LM, Demkowicz P, Chen L, et al. Evaluation of 16S rRNA gene sequencing for species and strain-level microbiome analysis. Nat Commun. 2019; 10(1): 5029.

[31] Chai X, Wang J, Li H, Gao C, Li S, Wei C, et al. Intratumor microbiome features reveal antitumor potentials of intrahepatic cholangiocarcinoma. Gut Microbes. 2023; 15(1): 2156255.

[32] Fu A, Yao B, Dong T, Chen Y, Yao J, Liu Y, et al. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell. 2022; 185(8): 1356–1372 e26.

[33] Liu W, Zhang X, Xu H, Li S, Lau HC, Chen Q, et al. Microbial Community Heterogeneity Within Colorectal Neoplasia and its Correlation With Colorectal Carcinogenesis. Gastroenterology. 2021; 160(7): 2395–2408.

[34] Clarridge JE, 3rd. Impact of 16S rRNA gene sequence analysis for identification of bacteria on clinical microbiology and infectious diseases. Clin Microbiol Rev. 2004; 17(4): 840–862, table of contents.

[35] Quince C, Walker AW, Simpson JT, Loman NJ, Segata N. Corrigendum: Shotgun metagenomics, from sampling to analysis. Nat Biotechnol. 2017; 35(12): 1211.

[36] Huang X, Chen C, Xie W, Zhou C, Tian X, Zhang Z, et al. Metagenomic Analysis of Intratumoral Microbiome Linking to Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer. Int J Radiat Oncol Biol Phys. 2023; 117(5): 1255–1269.

[37] Liu NN, Yi CX, Wei LQ, Zhou JA, Jiang T, Hu CC, et al. The intratumor mycobiome promotes lung cancer progression via myeloid-derived suppressor cells. Cancer Cell. 2023; 41(11): 1927–1944 e9.

[38] Zapatka M, Borozan I, Brewer DS, Iskar M, Grundhoff A, Alawi M, et al. The landscape of viral associations in human cancers. Nat Genet. 2020; 52(3): 320–330.

[39] Zhou X, Kandalai S, Hossain F, Zheng Q. Tumor microbiome metabolism: A game changer in cancer development and therapy. Front Oncol. 2022; 12: 933407.

[40] Mukherjee A, Reddy MS. Metatranscriptomics: an approach for retrieving novel eukaryotic genes from polluted and related environments. 3 Biotech. 2020; 10(2): 71.

[41] Ojala T, Kankuri E, Kankainen M. Understanding human health through metatranscriptomics. Trends Mol Med. 2023; 29(5): 376–389.

[42] Xie Y, Xie F, Zhou X, Zhang L, Yang B, Huang J, et al. Microbiota in Tumors: From Understanding to Application. Adv Sci (Weinh). 2022; 9(21): e2200470.

[43] Zhang N, Kandalai S, Zhou X, Hossain F, Zheng Q. Applying multi-omics toward tumor microbiome research. Imeta. 2023; 2(1): e73.

[44] Budding AE, Grasman ME, Lin F, Bogaards JA, Soeltan-Kaersenhout DJ. Vandenbroucke-Grauls CM, et al. IS-pro: high-throughput molecular fingerprinting of the intestinal microbiota. FASEB J. 2010; 24(11): 4556–4564.

[45] Budding AE, Hoogewerf M, Vandenbroucke-Grauls CM. Savelkoul PH. Automated Broad-Range Molecular Detection of Bacteria in Clinical Samples. J Clin Microbiol. 2016; 54(4): 934–943.

[46] Singer M, Koedooder R, Bos MP, Poort L, Schoenmakers S, Savelkoul PHM, et al. The profiling of microbiota in vaginal swab samples using 16S rRNA gene sequencing and IS-pro analysis. BMC Microbiol. 2021; 21(1): 100.

[47] Guo W, Zhang Y, Guo S, Mei Z, Liao H, Dong H, et al. Tumor microbiome contributes to an aggressive phenotype in the basal-like subtype of pancreatic cancer. Commun Biol. 2021; 4(1): 1019.

[48] Matturro B, Rossetti S, Leitão P. CAtalyzed Reporter Deposition Fluorescence In Situ Hybridization (CARD-FISH) for Complex Environmental Samples. Methods Mol Biol. 2021; 2246: 129–140.

[49] Zhang L, Xiao D, Cheng K. Proteomic analysis of microbial infections. Molecular Medical Microbiology. Elsevier; 2024. p. 1951–1963.

[50] Wu AH, French D. Implementation of liquid chromatography/mass spectrometry into the clinical laboratory. Clin Chim Acta. 2013; 420: 4–10.

[51] Qian X, Zhang HY, Li QL, Ma GJ, Chen Z, Ji XM, et al. Integrated microbiome, metabolome, and proteome analysis identifies a novel interplay among commensal bacteria, metabolites and candidate targets in non-small cell lung cancer. Clin Transl Med. 2022; 12(6): e947.

[52] Alharbi RA. Proteomics approach and techniques in identification of reliable biomarkers for diseases. Saudi J Biol Sci. 2020; 27(3): 968–974.

[53] Al-Amrani S, Al-Jabri Z. Al-Zaabi A, Alshekaili J, Al-Khabori M. Proteomics: Concepts and applications in human medicine. World J Biol Chem. 2021; 12(5): 57–69.

[54] Idle JR, Gonzalez FJJCm. Metabolomics. Cell Metab. 2007; 6(5): 348–351.

[55] Bauermeister A, Mannochio-Russo H. Costa-Lotufo LV, Jarmusch AK, Dorrestein PC. Mass spectrometry-based metabolomics in microbiome investigations. Nat Rev Microbiol. 2022; 20(3): 143–160.

[56] Bhosle A, Wang Y, Franzosa EA, Huttenhower C. Progress and opportunities in microbial community metabolomics. Curr Opin Microbiol. 2022; 70: 102195.

[57] Tang J. Microbial metabolomics. Curr Genomics. 2011; 12(6): 391–403.

[58] Daliri EB, Wei S, Oh DH, Lee BH. The human microbiome and metabolomics: Current concepts and applications. Crit Rev Food Sci Nutr. 2017; 57(16): 3565–3576.

[59] Zhu Z, Cai J, Hou W, Xu K, Wu X, Song Y, et al. Microbiome and spatially resolved metabolomics analysis reveal the anticancer role of gut Akkermansia muciniphila by crosstalk with intratumoral microbiota and reprogramming tumoral metabolism in mice. Gut Microbes. 2023; 15(1): 2166700.

[60] Cheng Y, He C, Wang M, Ma X, Mo F, Yang S, et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther. 2019; 4: 62.

[61] Zhang L, Wang R, Xie Z. The roles of DNA methylation on the promotor of the Epstein-Barr virus (EBV) gene and the genome in patients with EBV-associated diseases. Appl Microbiol Biotechnol. 2022; 106(12): 4413–4426.

[62] Zheng Q, Omans ND, Leicher R, Osunsade A, Agustinus AS, Finkin-Groner E. et al. Reversible histone glycation is associated with disease-related changes in chromatin architecture. Nat Commun. 2019; 10(1): 1289.

[63] Lüdtke TH, Wojahn I, Kleppa MJ, Schierstaedt J, Christoffels VM, Künzler P, et al. Combined genomic and proteomic approaches reveal DNA binding sites and interaction partners of TBX2 in the developing lung. Respir Res. 2021; 22(1): 85.

[64] Barhoum A, Luisa García-Betancourt M. Chapter 10 -Physicochemical characterization of nanomaterials: size, morphology, optical, magnetic, and electrical properties. In: Barhoum A, Makhlouf ASH, editors. Emerging Applications of Nanoparticles and Architecture Nanostructures. Elsevier; 2018. p. 279–304.

[65] Pope I, Tanner H, Masia F, Payne L, Arkill KP, Mantell J, et al. Correlative light-electron microscopy using small gold nanoparticles as single probes. Light Sci Appl. 2023; 12(1): 80.

[66] Huang Z, Mo S, Yan L, Wei X, Huang Y, Zhang L, et al. A Simple Culture Method Enhances the Recovery of Culturable Actinobacteria From Coastal Sediments. Front Microbiol. 2021; 12: 675048.

[67] Lewis WH, Tahon G, Geesink P, Sousa DZ, Ettema TJG. Innovations to culturing the uncultured microbial majority. Nat Rev Microbiol. 2021; 19(4): 225–240.

[68] Cross KL, Campbell JH, Balachandran M, Campbell AG, Cooper CJ, Griffen A, et al. Targeted isolation and cultivation of uncultivated bacteria by reverse genomics. Nat Biotechnol. 2019; 37(11): 1314–1321.

[69] LeSavage BL, Suhar RA, Broguiere N, Lutolf MP, Heilshorn SC. Next-generation cancer organoids. Nat Mater. 2022; 21(2): 143–159.

[70] Sule WF, Oluwayelu DO. Real-time RT-PCR for COVID-19 diagnosis: challenges and prospects. Pan Afr Med J. 2020; 35(Suppl 2): 121.

[71] Ahmed W, Bivins A, Metcalfe S, Smith WJM, Ziels R, Korajkic A, et al. RT-qPCR and ATOPlex sequencing for the sensitive detection of SARS-CoV-2 RNA for wastewater surveillance. Water Res. 2022; 220: 118621.

[72] Chen L, Chen H, Ye J, Ge Y, Wang H, Dai E, et al. Intratumoral expression of interleukin 23 variants using oncolytic vaccinia virus elicit potent antitumor effects on multiple tumor models via tumor microenvironment modulation. Theranostics. 2021; 11(14): 6668–6681.

[73] Kojabad AA, Farzanehpour M, Galeh HEG, Dorostkar R, Jafarpour A, Bolandian M, et al. Droplet digital PCR of viral DNA/RNA, current progress, challenges, and future perspectives. J Med Virol. 2021; 93(7): 4182–4197.

[74] Galimberti S, Balducci S, Guerrini F, Del Re M, Cacciola R. Digital Droplet PCR in Hematologic Malignancies: A New Useful Molecular Tool. Diagnostics (Basel). 2022; 12(6): 1305.

[75] Li CL, Ho MC, Lin YY, Tzeng ST, Chen YJ, Pai HY, et al. Cell-Free Virus-Host Chimera DNA From Hepatitis B Virus Integration Sites as a Circulating Biomarker of Hepatocellular Cancer. Hepatology. 2020; 72(6): 2063–2076.

[76] Zhao MH, Liu W, Zhang X, Zhang Y, Luo B. Epstein-Barr virus miR-BART2-5p and miR-BART11-5p regulate cell proliferation, apoptosis, and migration by targeting RB and p21 in gastric carcinoma. J Med Virol. 2023; 95(1): e28338.

[77] Pedersen JC. Hemagglutination-inhibition test for avian influenza virus subtype identification and the detection and quantitation of serum antibodies to the avian influenza virus. Methods Mol Biol. 2008; 436: 53–66.

[78] Sethi J, Pei D, Hirshaut Y. Choice and specificity of complement in complement fixation assay. J Clin Microbiol. 1981; 13(5): 888–890.

[79] Westhaus S, Rabenau HF. Neutralization Assay for SARS-CoV-2 Infection: Plaque Reduction Neutralization Test. Methods Mol Biol. 2022; 2452: 353–360.

[80] Tabatabaei MS, Ahmed M. Enzyme-Linked Immunosorbent Assay (ELISA). Methods Mol Biol. 2022; 2508: 115–134.

[81] Burckhardt CJ, Minna JD, Danuser G. Co-immunoprecipitation and semi-quantitative immunoblotting for the analysis of protein-protein interactions. STAR Protoc. 2021; 2(3): 100644.

[82] Granzow H, Klupp BG, Mettenleiter TC. Entry of pseudorabies virus: an immunogold-labeling study. J Virol. 2005; 79(5): 3200–3205.

[83] Tanaka S, Nishii H, Ito S, Kameya-Iwaki M. Sommartya P. Detection of Cymbidium Mosaic Potexvirus and Odontoglossum Ringspot Tobamovirus from Thai Orchids by Rapid Immunofilter Paper Assay. Plant Dis. 1997; 81(2): 167–170.

[84] Eun AJ, Wong SM. Detection of cymbidium mosaic potexvirus and odontoglossum ringspot tobamovirus using immuno-capillary zone electrophoresis. Phytopathology. 1999; 89(6): 522–528.

[85] Ryazantsev DY, Voronina DV, Zavriev SK. Immuno-PCR: Achievements and Perspectives. Biochemistry (Mosc). 2016; 81(13): 1754–1770.

[86] Trent DW, Harvey CL, Qureshi A, LeStourgeon D. Solid-phase radioimmunoassay for antibodies to flavivirus structural and nonstructural proteins. Infect Immun. 1976; 13(5): 1325–1333.

[87] Zhang DY, Chen SX, Yin P. Optimizing the specificity of nucleic acid hybridization. Nat Chem. 2012; 4(3): 208–214.

[88] Shirasawa H, Tomita Y, Kubota K, Kasai T, Sekiya S, Takamizawa H, et al. Detection of human papillomavirus type 16 DNA and evidence for integration into the cell DNA in cervical dysplasia. J Gen Virol. 1986; 67(Pt 9): 2011–2015.

[89] Pan ST, Chang WS, Murphy M, Martinez A, Chuang SS. Cutaneous peripheral T-cell lymphoma of cytotoxic phenotype mimicking extranodal NK/T-cell lymphoma. Am J Dermatopathol. 2011; 33(2): e17–e20.

[90] Huang X-M, Wei SG, Wang LF. Reversal of malignant phenotype of human hepatoma cells by antisense: c-ets-2, c-myc an. N-ras. Zhonghua Zhongliu Zazhi. 1994; 16(4): 243–246.

[91] Manjunath N, Kaur H, Bala S, Kaur R, Bhargava V, Rath GK, et al. Detection of herpes simplex virus type 2 DNA in uterine cervix lesions using cloned Bgl II N fragment of HSV-2 DNA as a probe. Indian J Med Res. 1988; 87: 127–133.

[92] Chen X, Yang Z. Chapter 3 -Biosensors for single-cell metabolomic characterization. In: Chen J, Lu Y, editors. Biosensors for Single-Cell Analysis. Academic Press; 2022. p. 37–70.

[93] Yasuga H, Shoji K, Koiwai K, Kawano R. New Sensing Technologies: Microtas/NEMS/MEMS. In: Narayan R, editor. Encyclopedia of Sensors and Biosensors (First Edition). Oxford: Elsevier; 2023. p. 526–540.

[94] Ghaddar B, Biswas A, Harris C, Omary MB, Carpizo DR, Blaser MJ, et al. Tumor microbiome links cellular programs and immunity in pancreatic cancer. Cancer Cell. 2022; 40(10): 1240–1253 e5.

[95] Wu F, Fan J, He Y, Xiong A, Yu J, Li Y, et al. Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer. Nat Commun. 2021; 12(1): 2540.

[96] Longo SK, Guo MG, Ji AL, Khavari PA. Integrating single-cell and spatial transcriptomics to elucidate intercellular tissue dynamics. Nat Rev Genet. 2021; 22(10): 627–644.

[97] Moncada R, Barkley D, Wagner F, Chiodin M, Devlin JC, Baron M, et al. Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas. Nat Biotechnol. 2020; 38(3): 333–342.

[98] Ai B, Liang Y, Yan T, Lei Y. Exploration of immune cell heterogeneity by single-cell RNA sequencing and identification of secretory leukocyte protease inhibitor as an oncogene in pancreatic cancer. Environ Toxicol. 2024.

[99] Liu Z, Zhang Z, Zhang Y, Zhou W, Zhang X, Peng C, et al. Spatial transcriptomics reveals that metabolic characteristics define the tumor immunosuppression microenvironment via iCAF transformation in oral squamous cell carcinoma. Int J Oral Sci. 2024; 16(1): 9.

[100] Jain S, Rick JW, Joshi RS, Beniwal A, Spatz J, Gill S, et al. Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects. J Clin Invest. 2023; 133(5): e147087.

[101] Ji AL, Rubin AJ, Thrane K, Jiang S, Reynolds DL, Meyers RM, et al. Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma. Cell. 2020; 182(2): 497–514 e22.

[102] Qi J, Sun H, Zhang Y, Wang Z, Xun Z, Li Z, et al. Single-cell and spatial analysis reveal interaction of FAP(+) fibroblasts and SPP1(+) macrophages in colorectal cancer. Nat Commun. 2022; 13(1): 1742.

[103] Wu SZ, Al-Eryani G. Roden DL, Junankar S, Harvey K, Andersson A, et al. A single-cell and spatially resolved atlas of human breast cancers. Nat Genet. 2021; 53(9): 1334–1347.

[104] Wang G, Zhao J, Yan Y, Wang Y, Wu AR, Yang C. Construction of a 3D whole organism spatial atlas by joint modelling of multiple slices with deep neural networks. Nat Mach Intell. 2023; 5(11): 1200–1213.

[105] Wang B, Lin AE, Yuan J, Novak KE, Koch MD, Wingreen NS, et al. Single-cell massively-parallel multiplexed microbial sequencing (M3-seq) identifies rare bacterial populations and profiles phage infection. Nat Microbiol. 2023; 8(10): 1846–1862.

[106] Tang XY, Wu S, Wang D, Chu C, Hong Y, Tao M, et al. Human organoids in basic research and clinical applications. Signal Transduct Target Ther. 2022; 7(1): 168.

[107] Yang S, Hu H, Kung H, Zou R, Dai Y, Hu Y, et al. Organoids: The current status and biomedical applications. MedComm (2020). 2023; 4(3): e274.

[108] Yang R, Yu Y. Patient-derived organoids in translational oncology and drug screening. Cancer Lett. 2023; 562: 216180.

[109] Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G, Weeber F, et al. A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity. Cell. 2018; 172(1-2): 373–386 e10.

[110] Ganesh K, Wu C, O’Rourke KP, Szeglin BC, Zheng Y, Sauve CG, et al. A rectal cancer organoid platform to study individual responses to chemoradiation. Nat Med. 2019; 25(10): 1607–1614.

[111] Below CR, Kelly J, Brown A, Humphries JD, Hutton C, Xu J, et al. A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids. Nat Mater. 2022; 21(1): 110–119.

[112] Kim M, Mun H, Sung CO, Cho EJ, Jeon HJ, Chun SM, et al. Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nat Commun. 2019; 10(1): 3991.

[113] Tiriac H, Belleau P, Engle DD, Plenker D, Deschenes A, Somerville TDD, et al. Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov. 2018; 8(9): 1112–1129.

[114] Kopper O, de Witte CJ, Lohmussaar K, Valle-Inclan JE. Hami N, Kester L, et al. An organoid platform for ovarian cancer captures intra-and interpatient heterogeneity. Nat Med. 2019; 25(5): 838–849.

[115] Jacob F, Salinas RD, Zhang DY, Nguyen PTT, Schnoll JG, Wong SZH, et al. A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter-and Intra-tumoral Heterogeneity. Cell. 2020; 180(1): 188–204 e22.

[116] Driehuis E, Kretzschmar K, Clevers H. Establishment of patient-derived cancer organoids for drug-screening applications. Nat Protoc. 2020; 15(10): 3380–3409.

[117] Yuki K, Cheng N, Nakano M, Kuo CJ. Organoid Models of Tumor Immunology. Trends Immunol. 2020; 41(8): 652–664.

[118] Neal JT, Li X, Zhu J, Giangarra V, Grzeskowiak CL, Ju J, et al. Organoid Modeling of the Tumor Immune Microenvironment. Cell. 2018; 175(7): 1972–1988 e16.

[119] Puschhof J, Pleguezuelos-Manzano C. Clevers H. Organoids and organs-on-chips: Insights into human gut-microbe interactions. Cell Host Microbe. 2021; 29(6): 867–878.

[120] Su CY, Burchett A, Dunworth M, Choi JS, Ewald AJ, Ahn EH, et al. Engineering a 3D collective cancer invasion model with control over collagen fiber alignment. Biomaterials. 2021; 275: 120922.

[121] Dabbagh SR, Sarabi MR, Birtek MT, Seyfi S, Sitti M, Tasoglu S. 3D-printed microrobots from design to translation. Nat Commun. 2022; 13(1): 5875.

[122] Zimdahl H, Hübner N. Gene Chip Technology and Its Application to Molecular Medicine. Encyclopedic Reference of Genomics and Proteomics in Molecular Medicine. 2005: 650–655.

[123] Chan LC, Kalyanasundram J, Leong SW, Masarudin MJ, Veerakumarasivam A, Yusoff K, et al. Persistent Newcastle disease virus infection in bladder cancer cells is associated with putative pro-survival and anti-viral transcriptomic changes. BMC Cancer. 2021; 21(1): 625.

[124] Yen CJ, Ai YL, Tsai HW, Chan SH, Yen CS, Cheng KH, et al. Hepatitis B virus surface gene pre-S(2) mutant as a high-risk serum marker for hepatoma recurrence after curative hepatic resection. Hepatology. 2018; 68(3): 815–826.

[125] Chen EC, Miller SA, DeRisi JL, Chiu CY. Using a pan-viral microarray assay (Virochip) to screen clinical samples for viral pathogens. J Vis Exp. 2011; (50): 2536.

[126] Yang Y, Chu B, Cheng J, Tang J, Song B, Wang H, et al. Bacteria eat nanoprobes for aggregation-enhanced imaging and killing diverse microorganisms. Nat Commun. 2022; 13(1): 1255.

[127] Zhu K, Schaffer AA, Robinson W, Xu J, Ruppin E, Ergun AF, et al. Strain level microbial detection and quantification with applications to single cell metagenomics. Nat Commun. 2022; 13(1): 6430.

[128] Wang P, Zhang S, He G, Du M, Qi C, Liu R, et al. microbioTA: an atlas of the microbiome in multiple disease tissues of Homo sapiens and Mus musculus. Nucleic Acids Res. 2023; 51(D1): D1345–D1352.

[129] Dohlman AB, Arguijo Mendoza D, Ding S, Gao M, Dressman H, Iliev ID, et al. The cancer microbiome atlas: a pan-cancer comparative analysis to distinguish tissue-resident microbiota from contaminants. Cell Host Microbe. 2021; 29(2): 281–298 e5.

[130] Tan CCS, Ko KKK, Chen H, Liu J, Loh M, Consortium SGKH, et al. No evidence for a common blood microbiome based on a population study of 9, 770 healthy humans. Nat Microbiol. 2023; 8(5): 973–985.

[131] Wong-Rolle A, Wei HK, Zhao C, Jin C. Unexpected guests in the tumor microenvironment: microbiome in cancer. Protein Cell. 2021; 12(5): 426–435.

[132] Jiang M, Yang Z, Dai J, Wu T, Jiao Z, Yu Y, et al. Intratumor microbiome: selective colonization in the tumor microenvironment and a vital regulator of tumor biology. MedComm (2020). 2023; 4(5): e376.

[133] Dejea CM, Fathi P, Craig JM, Boleij A, Taddese R, Geis AL, et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science. 2018; 359(6375): 592–597.

[134] Wilson MR, Jiang Y, Villalta PW, Stornetta A, Boudreau PD, Carra A, et al. The human gut bacterial genotoxin colibactin alkylates DNA. Science. 2019; 363(6428): eaar7785.

[135] Allen J, Sears CL. Impact of the gut microbiome on the genome and epigenome of colon epithelial cells: contributions to colorectal cancer development. Genome Med. 2019; 11(1): 11.

[136] Urbaniak C, Gloor GB, Brackstone M, Scott L, Tangney M, Reid G. The Microbiota of Breast Tissue and Its Association with Breast Cancer. Appl Environ Microbiol. 2016; 82(16): 5039–5048.

[137] Irrazabal T, Thakur BK, Kang M, Malaise Y, Streutker C, Wong EOY, et al. Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer. Nat Commun. 2020; 11(1): 1802.

[138] Chattopadhyay I, Verma M, Panda M. Role of Oral Microbiome Signatures in Diagnosis and Prognosis of Oral Cancer. Technol Cancer Res Treat. 2019; 18: 1533033819867354.

[139] DeCaprio JA. Molecular Pathogenesis of Merkel Cell Carcinoma. Annu Rev Pathol. 2021; 16: 69–91.

[140] Shuda M, Feng H, Kwun HJ, Rosen ST, Gjoerup O, Moore PS, et al. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci U S A. 2008; 105(42): 16272–16277.

[141] Wallace NA, Khanal S, Robinson KL, Wendel SO, Messer JJ, Galloway DA. High-Risk Alphapapillomavirus Oncogenes Impair the Homologous Recombination Pathway. J Virol. 2017; 91(20): e01084–17.

[142] Nicot C. HTLV-I Tax-Mediated Inactivation of Cell Cycle Checkpoints and DNA Repair Pathways Contribute to Cellular Transformation: “A Random Mutagenesis Model”. J Cancer Sci. 2015; 2(2). 10.13188/2377-9292.1000009

[143] Peng Y, Wang Y, Zhou C, Mei W, Zeng C. PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway? Front Oncol. 2022; 12: 819128.

[144] Tsay JJ, Wu BG, Badri MH, Clemente JC, Shen N, Meyn P, et al. Airway Microbiota Is Associated with Upregulation of the PI3K Pathway in Lung Cancer. Am J Respir Crit Care Med. 2018; 198(9): 1188–1198.

[145] Gustafson AM, Soldi R, Anderlind C, Scholand MB, Qian J, Zhang X, et al. Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci Transl Med. 2010; 2(26): 26ra5.

[146] Zhang L, Wu J, Ling MT, Zhao L, Zhao KN. The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses. Mol Cancer. 2015; 14: 87.

[147] Olagnier D, Sze A, Bel Hadj S, Chiang C, Steel C, Han X, et al. HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells. PLoS Pathog. 2014; 10(12): e1004575.

[148] Chang HH, Ganem D. A unique herpesviral transcriptional program in KSHV-infected lymphatic endothelial cells leads to mTORC1 activation and rapamycin sensitivity. Cell Host Microbe. 2013; 13(4): 429–440.

[149] Mullen PJ, Christofk HR. The Metabolic Relationship Between Viral Infection and Cancer. Annual Review of Cancer Biology. 2022; 6(1): 1–15.

[150] Xue C, Yao Q, Gu X, Shi Q, Yuan X, Chu Q, et al. Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer. Signal Transduct Target Ther. 2023; 8(1): 204.

[151] Bromberg J, Darnell JE, Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene. 2000; 19(21): 2468–2473.

[152] Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL, Jr. Microbial complexes in subgingival plaque. J Clin Periodontol. 1998; 25(2): 134–144.

[153] Katz J, Onate MD, Pauley KM, Bhattacharyya I, Cha S. Presence of Porphyromonas gingivalis in gingival squamous cell carcinoma. Int J Oral Sci. 2011; 3(4): 209–215.

[154] Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. 2013; 14(2): 207–215.

[155] Gao Y, Huang E, Zhang H, Wang J, Wu N, Chen X, et al. Crosstalk between Wnt/beta-catenin and estrogen receptor signaling synergistically promotes osteogenic differentiation of mesenchymal progenitor cells. PLoS One. 2013; 8(12): e82436.

[156] Garrett WS. Cancer and the microbiota. Science. 2015; 348(6230): 80–86.

[157] Xu J, Prosperi JR, Choudhury N, Olopade OI, Goss KH. beta-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells. PLoS One. 2015; 10(2): e0117097.

[158] Jha HC, Banerjee S, Robertson ES. The Role of Gammaherpesviruses in Cancer Pathogenesis. Pathogens. 2016; 5(1): 18.

[159] Angelova M, Ferris M, Swan KF, McFerrin HE, Pridjian G, Morris CA, et al. Kaposi’s sarcoma-associated herpesvirus G-protein coupled receptor activates the canonical Wnt/β-catenin signaling pathway. Virol J. 2014; 11: 218.

[160] Ma G, Yasunaga J, Fan J, Yanagawa S, Matsuoka M. HTLV-1 bZIP factor dysregulates the Wnt pathways to support proliferation and migration of adult T-cell leukemia cells. Oncogene. 2013; 32(36): 4222–4230.

[161] Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov. 2014; 13(12): 928–942.

[162] Kim HJ, Bar-Sagi D. Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol. 2004; 5(6): 441–450.

[163] 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(21): 5338–5356.e21.

[164] Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, et al. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene. 2010; 29(27): 3881–3895.

[165] Wang Y, Alam GN, Ning Y, Visioli F, Dong Z, Nor JE, et al. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. Cancer Res. 2012; 72(20): 5396–5406.

[166] Dang N, Meng X, Qin G, An Y, Zhang Q, Cheng X, et al. alpha5-nAChR modulates melanoma growth through the Notch1 signaling pathway. J Cell Physiol. 2020; 235(11): 7816–7826.

[167] Wang D, DuBois RN. Immunosuppression associated with chronic inflammation in the tumor microenvironment. Carcinogenesis. 2015; 36(10): 1085–1093.

[168] Cutolo M, Paolino S, Pizzorni C. Possible contribution of chronic inflammation in the induction of cancer in rheumatic diseases. Clin Exp Rheumatol. 2014; 32(6): 839–847.

[169] Bhatelia K, Singh K, Singh R. TLRs: linking inflammation and breast cancer. Cell Signal. 2014; 26(11): 2350–2357.

[170] Valguarnera E, Wardenburg JB. Good Gone Bad: One Toxin Away From Disease for Bacteroides fragilis. J Mol Biol. 2020; 432(4): 765–785.

[171] Shalapour S, Karin M. Cruel to Be Kind: Epithelial, Microbial, and Immune Cell Interactions in Gastrointestinal Cancers. Annu Rev Immunol. 2020; 38: 649–671.

[172] Chen Y, Liu B, Wei Y, Kuang DM. Influence of gut and intratumoral microbiota on the immune microenvironment and anti-cancer therapy. Pharmacol Res. 2021; 174: 105966.

[173] Choi Y, Lichterman JN, Coughlin LA, Poulides N, Li W, Del Valle P, et al. Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity. Sci Immunol. 2023; 8(81): eabo2003.

[174] Shi Y, Zheng W, Yang K, Harris KG, Ni K, Xue L, et al. Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling. J Exp Med. 2020; 217(5): e20192282.

[175] Le Noci V, Guglielmetti S, Arioli S, Camisaschi C, Bianchi F, Sommariva M, et al. Modulation of Pulmonary Microbiota by Antibiotic or Probiotic Aerosol Therapy: A Strategy to Promote Immunosurveillance against Lung Metastases. Cell Rep. 2018; 24(13): 3528–3538.

[176] Ohadian Moghadam S, Momeni SA. Human microbiome and prostate cancer development: current insights into the prevention and treatment. Front Med. 2021; 15(1): 11–32.

[177] Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J, Gamliel M, et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 2015; 42(2): 344–355.

[178] Abed J, Emgard JE, Zamir G, Faroja M, Almogy G, Grenov A, et al. Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc. Cell Host Microbe. 2016; 20(2): 215–225.

[179] Wen L, Mu W, Lu H, Wang X, Fang J, Jia Y, et al. Porphyromonas gingivalis Promotes Oral Squamous Cell Carcinoma Progression in an Immune Microenvironment. J Dent Res. 2020; 99(6): 666–675.

[180] Zhang B, Cheng P. Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy. Mol Cancer. 2020; 19(1): 158.

[181] Wang Y, Guo W, Wu X, Zhang Y, Mannion C, Brouchkov A, et al. Oncolytic Bacteria and their potential role in bacterium-mediated tumour therapy: a conceptual analysis. J Cancer. 2019; 10(19): 4442–4454.

[182] 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(7852): 138–143.

[183] Fluckiger A, Daillère R, Sassi M, Sixt BS, Liu P, Loos F, et al. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage. Science. 2020; 369(6506): 936–942.

[184] Bessell CA, Isser A, Havel JJ, Lee S, Bell DR, Hickey JW, et al. Commensal bacteria stimulate antitumor responses via T cell cross-reactivity. JCI Insight. 2020; 5(8): e135597.

[185] Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018; 360(6391): eaan5931.

[186] Parida S, Siddharth S, Xia Y, Sharma D. Concomitant analyses of intratumoral microbiota and genomic features reveal distinct racial differences in breast cancer. NPJ Breast Cancer. 2023; 9(1): 4.

[187] Choi JK, Naffouje SA, Goto M, Wang J, Christov K, Rademacher DJ, et al. Cross-talk between cancer and Pseudomonas aeruginosa mediates tumor suppression. Commun Biol. 2023; 6(1): 16.

[188] 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(21): 5338–5356 e21.

[189] 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(6510): 1481–1489.

[190] Drobner JC, Lichtbroun BJ, Singer EA, Ghodoussipour S. Examining the Role of Microbiota-Centered Interventions in Cancer Therapeutics: Applications for Urothelial Carcinoma. Technol Cancer Res Treat. 2023; 22: 15330338231164196.

[191] Kang X, Liu C, Ding Y, Ni Y, Ji F, Lau HCH, et al. Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8(+) T cells. Gut. 2023; 72(11): 2112–2122.

[192] Lu C, Liu Y, Ali NM, Zhang B, Cui X. The role of innate immune cells in the tumor microenvironment and research progress in anti-tumor therapy. Front Immunol. 2022; 13: 1039260.

[193] Chmiela M, Walczak N, Rudnicka K. Helicobacter pylori outer membrane vesicles involvement in the infection development and Helicobacter pylori-related diseases. J Biomed Sci. 2018; 25(1): 78.

[194] Gonzalez MF, Diaz P, Sandoval-Borquez A. Herrera D, Quest AFG. Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development. Int J Mol Sci. 2021; 22(9): 4823.

[195] 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(6264): 1084–1089.

[196] 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(6264): 1079–1084.

[197] 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(6371): 104–108.

[198] Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol. 2018; 29(6): 1437–1444.

[199] Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021; 371(6529): 595–602.

[200] Derosa L, Routy B, Thomas AM, Iebba V, Zalcman G, Friard S, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med. 2022; 28(2): 315–324.

[201] Bae M, Cassilly CD, Liu X, Park SM, Tusi BK, Chen X, et al. Akkermansia muciniphila phospholipid induces homeostatic immune responses. Nature. 2022; 608(7921): 168–173.

[202] Lu Y, Yuan X, Wang M, He Z, Li H, Wang J, et al. Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies. J Hematol Oncol. 2022; 15(1): 47.

[203] Wang T, Gnanaprakasam JNR, Chen X, Kang S, Xu X, Sun H, et al. Inosine is an alternative carbon source for CD8(+)-T-cell function under glucose restriction. Nat Metab. 2020; 2(7): 635–647.

[204] Oh M, Zhang L. DeepGeni: deep generalized interpretable autoencoder elucidates gut microbiota for better cancer immunotherapy. Sci Rep. 2023; 13(1): 4599.

[205] Hezaveh K, Shinde RS, Klötgen A, Halaby MJ, Lamorte S, Ciudad MT, et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity. 2022; 55(2): 324–340.e8.

[206] Fong W, Li Q, Ji F, Liang W, Lau HCH, Kang X, et al. Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis. Gut. 2023; 72(12): 2272–2285.

[207] Jiang SS, Xie YL, Xiao XY, Kang ZR, Lin XL, Zhang L, et al. Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer. Cell Host Microbe. 2023; 31(5): 781–797 e9.

[208] 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(6371): 97–103.

[209] Park JS, Gazzaniga FS, Wu M, Luthens AK, Gillis J, Zheng W, et al. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance. Nature. 2023; 617(7960): 377–385.

[210] Anand U, Dey A, Chandel AKS, Sanyal R, Mishra A, Pandey DK, et al. Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics. Genes Dis. 2023; 10(4): 1367–1401.

[211] Ramos A, Sadeghi S, Tabatabaeian H. Battling Chemoresistance in Cancer: Root Causes and Strategies to Uproot Them. Int J Mol Sci. 2021; 22(17): 9451.

[212] Guthrie L, Gupta S, Daily J, Kelly L. Human microbiome signatures of differential colorectal cancer drug metabolism. NPJ Biofilms Microbiomes. 2017; 3: 27.

[213] Tintelnot J, Xu Y, Lesker TR, Schönlein M, Konczalla L, Giannou AD, et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature. 2023; 615(7950): 168–174.

[214] Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013; 342(6161): 971–976.

[215] Daillère R, Vétizou M, Waldschmitt N, Yamazaki T, Isnard C, Poirier-Colame V. et al. Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects. Immunity. 2016; 45(4): 931–943.

[216] Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013; 342(6161): 967–970.

[217] Aykut B, Pushalkar S, Chen R, Li Q, Abengozar R, Kim JI, et al. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature. 2019; 574(7777): 264–267.

[218] Pomella S, Cassandri M, Melaiu O, Marampon F, Gargari M, Campanella V, et al. DNA Damage Response Gene Signature as Potential Treatment Markers for Oral Squamous Cell Carcinoma. Int J Mol Sci. 2023; 24(3): 2673.

[219] Liu J, Liu C, Yue J. Radiotherapy and the gut microbiome: facts and fiction. Radiat Oncol. 2021; 16(1): 9.

[220] Dong J, Li Y, Xiao H, Cui M, Fan S. Commensal microbiota in the digestive tract: a review of its roles in carcinogenesis and radiotherapy. Cancer Biol Med. 2021; 19(1): 43–55.

[221] Reis Ferreira M, Pasto A, Ng T, Patel V, Guerrero Urbano T, Sears C, et al. The microbiota and radiotherapy for head and neck cancer: What should clinical oncologists know? Cancer Treat Rev. 2022; 109: 102442.

[222] Uribe-Herranz M, Rafail S, Beghi S, Gil-de-Gómez L, Verginadis I, Bittinger K, et al. Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response. J Clin Invest. 2020; 130(1): 466–479.

[223] Shiao SL, Kershaw KM, Limon JJ, You S, Yoon J, Ko EY, et al. Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy. Cancer Cell. 2021; 39(9): 1202–1213.e6.

[224] Guo H, Chou WC, Lai Y, Liang K, Tam JW, Brickey WJ, et al. Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites. Science. 2020; 370(6516): eaay9097.

[225] Teng H, Wang Y, Sui X, Fan J, Li S, Lei X, et al. Gut microbiota-mediated nucleotide synthesis attenuates the response to neoadjuvant chemoradiotherapy in rectal cancer. Cancer Cell. 2023; 41(1): 124–138.e6.

[226] Colbert LE, El Alam MB, Wang R, Karpinets T, Lo D, Lynn EJ, et al. Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring. Cancer Cell. 2023; 41(11): 1945–1962 e11.

[227] Eaton SE, Kaczmarek J, Mahmood D, McDiarmid AM, Norarfan AN, Scott EG, et al. Exploiting dietary fibre and the gut microbiota in pelvic radiotherapy patients. Br J Cancer. 2022; 127(12): 2087–2098.

[228] Poonacha KNT, Villa TG, Notario V. The Interplay among Radiation Therapy, Antibiotics and the Microbiota: Impact on Cancer Treatment Outcomes. Antibiotics (Basel). 2022; 11(3): 331.

[229] Cui M, Xiao H, Li Y, Zhou L, Zhao S, Luo D, et al. Faecal microbiota transplantation protects against radiation-induced toxicity. EMBO Mol Med. 2017; 9(4): 448–461.

[230] Xiao H, Fan Y, Li Y, Dong J, Zhang S, Wang B, et al. Oral microbiota transplantation fights against head and neck radiotherapy-induced oral mucositis in mice. Comput Struct Biotechnol J. 2021; 19: 5898–5910.

[231] Mackowiak PA. Recycling metchnikoff: probiotics, the intestinal microbiome and the quest for long life. Front Public Health. 2013; 1: 52.

[232] Cavaillon JM, Legout S. Centenary of the death of Elie Metchnikoff: a visionary and an outstanding team leader. Microbes Infect. 2016; 18(10): 577–594.

[233] Suez J, Zmora N, Segal E, Elinav E. The pros, cons, and many unknowns of probiotics. Nat Med. 2019; 25(5): 716–729.

[234] Fuller R. History and development of probiotics. In: Fuller R, editor. Probiotics: The scientific basis. Dordrecht: Springer Netherlands; 1992. p. 1–8.

[235] Lim CC, Ferguson LR, Tannock GW. Dietary fibres as “prebiotics”: implications for colorectal cancer. Mol Nutr Food Res. 2005; 49(6): 609–619.

[236] Geier MS, Butler RN, Howarth GS. Probiotics, prebiotics and synbiotics: a role in chemoprevention for colorectal cancer? Cancer Biol Ther. 2006; 5(10): 1265–1269.

[237] Chong ES. A potential role of probiotics in colorectal cancer prevention: review of possible mechanisms of action. World J Microbiol Biotechnol. 2014; 30(2): 351–374.

[238] Gianotti L, Morelli L, Galbiati F, Rocchetti S, Coppola S, Beneduce A, et al. A randomized double-blind trial on perioperative administration of probiotics in colorectal cancer patients. World J Gastroenterol. 2010; 16(2): 167–175.

[239] de Moreno de LeBlanc A, Matar C, Perdigon G. The application of probiotics in cancer. Br J Nutr. 2007; 98(Suppl 1): S105–S110.

[240] Commane DM, Shortt CT, Silvi S, Cresci A, Hughes RM, Rowland IR. Effects of fermentation products of pro-and prebiotics on trans-epithelial electrical resistance in an in vitro model of the colon. Nutr Cancer. 2005; 51(1): 102–109.

[241] Kumar M, Kumar A, Nagpal R, Mohania D, Behare P, Verma V, et al. Cancer-preventing attributes of probiotics: an update. Int J Food Sci Nutr. 2010; 61(5): 473–496.

[242] Chen CC, Lin WC, Kong MS, Shi HN, Walker WA, Lin CY, et al. Oral inoculation of probiotics Lactobacillus acidophilus NCFM suppresses tumour growth both in segmental orthotopic colon cancer and extra-intestinal tissue. Br J Nutr. 2012; 107(11): 1623–1634.

[243] Uccello M, Malaguarnera G, Basile F, D’Agata V, Malaguarnera M, Bertino G, et al. Potential role of probiotics on colorectal cancer prevention. BMC Surg. 2012; 12(Suppl 1): S35.

[244] Noor S, Ali S, Riaz S, Sardar I, Farooq MA, Sajjad A. Chemopreventive role of probiotics against cancer: a comprehensive mechanistic review. Mol Biol Rep. 2023; 50(1): 799–814.

[245] Rafter J. Probiotics and colon cancer. Best Pract Res Clin Gastroenterol. 2003; 17(5): 849–859.

[246] Shi L, Sheng J, Chen G, Zhu P, Shi C, Li B, et al. Combining IL-2-based immunotherapy with commensal probiotics produces enhanced antitumor immune response and tumor clearance. J Immunother Cancer. 2020; 8(2): e000973.

[247] Zhang Q, Zhao Q, Li T, Lu L, Wang F, Zhang H, et al. Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8(+) T cell immunity. Cell Metab. 2023; 35(6): 943–960 e9.

[248] Raman M, Ambalam P, Kondepudi KK, Pithva S, Kothari C, Patel AT, et al. Potential of probiotics, prebiotics and synbiotics for management of colorectal cancer. Gut Microbes. 2013; 4(3): 181–192.

[249] Liong MT. Roles of probiotics and prebiotics in colon cancer prevention: Postulated mechanisms and in-vivo evidence. Int J Mol Sci. 2008; 9(5): 854–863.

[250] Redman MG, Ward EJ, Phillips RS. The efficacy and safety of probiotics in people with cancer: a systematic review. Ann Oncol. 2014; 25(10): 1919–1929.

[251] Tian Y, Li M, Song W, Jiang R, Li YQ. Effects of probiotics on chemotherapy in patients with lung cancer. Oncol Lett. 2019; 17(3): 2836–2848.

[252] van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013; 368(5): 407–415.

[253] Xu MQ, Cao HL, Wang WQ, Wang S, Cao XC, Yan F, et al. Fecal microbiota transplantation broadening its application beyond intestinal disorders. World J Gastroenterol. 2015; 21(1): 102–111.

[254] Rosshart SP, Vassallo BG, Angeletti D, Hutchinson DS, Morgan AP, Takeda K, et al. Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance. Cell. 2017; 171(5): 1015–1028 e13.

[255] Yao B, Cai Y, Wang W, Deng J, Zhao L, Han Z, et al. The Effect of Gut Microbiota on the Progression of Intervertebral Disc Degeneration. Orthop Surg. 2023; 15(3): 858–867.

[256] Wang L, Wei Z, Pan F, Song C, Peng L, Yang Y, et al. Case report: Fecal microbiota transplantation in refractory ankylosing spondylitis. Front Immunol. 2023; 14: 1093233.

[257] Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, et al. Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. Cell. 2019; 178(4): 795–806 e12.

[258] 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(6529): 602–609.

[259] Wang Z, Qin X, Hu D, Huang J, Guo E, Xiao R, et al. Akkermansia supplementation reverses the tumor-promoting effect of the fecal microbiota transplantation in ovarian cancer. Cell Rep. 2022; 41(13): 111890.

[260] Quesada-Vázquez S, Castells-Nobau A. Latorre J, Oliveras-Cañellas N, Puig-Parnau I. Tejera N, et al. Potential therapeutic implications of histidine catabolism by the gut microbiota in NAFLD patients with morbid obesity. Cell Rep Med. 2023; 4(12): 101341.

[261] Bustamante JM, Dawson T, Loeffler C, Marfori Z, Marchesi JR, Mullish BH, et al. Impact of Fecal Microbiota Transplantation on Gut Bacterial Bile Acid Metabolism in Humans. Nutrients. 2022; 14(24): 5200.

[262] Zheng L, Ji YY, Wen XL, Duan SL. Fecal microbiota transplantation in the metabolic diseases: Current status and perspectives. World J Gastroenterol. 2022; 28(23): 2546–2560.

[263] Pawelek JM, Low KB, Bermudes D. Tumor-targeted Salmonella as a novel anticancer vector. Cancer Res. 1997; 57(20): 4537–4544.

[264] Fan JX, Peng MY, Wang H, Zheng HR, Liu ZL, Li CX, et al. Engineered Bacterial Bioreactor for Tumor Therapy via Fenton-Like Reaction with Localized H(2) O(2) Generation. Adv Mater. 2019; 31(16): e1808278.

[265] Huang C, Wang FB, Liu L, Jiang W, Liu W, Ma W, et al. Hypoxic Tumor Radiosensitization Using Engineered Probiotics. Adv Healthc Mater. 2021; 10(10): e2002207.

[266] Liu SC, Minton NP, Giaccia AJ, Brown JM. Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Therapy. 2002; 9(4): 291–296.

[267] Bai RL, Chen NF, Li LY, Cui JW. A brand new era of cancer immunotherapy: breakthroughs and challenges. Chin Med J (Engl). 2021; 134(11): 1267–1275.

[268] Zhou S, Gravekamp C, Bermudes D, Liu K. Tumour-targeting bacteria engineered to fight cancer. Nat Rev Cancer. 2018; 18(12): 727–743.

[269] He L, Yang H, Tang J, Liu Z, Chen Y, Lu B, et al. Intestinal probiotics E. coli Nissle 1917 as a targeted vehicle for delivery of p53 and Tum-5 to solid tumors for cancer therapy. J Biol Eng. 2019; 13: 58.

[270] Shi LL, Sheng JY, Wang ML, Luo H, Zhu J, Zhang BX, et al. Combination Therapy of TGF-beta Blockade and Commensal-derived Probiotics Provides Enhanced Antitumor Immune Response and Tumor Suppression. Theranostics. 2019; 9(14): 4115–4129.

[271] Tang Q, Sun S, Wang P, Sun L, Wang Y, Zhang L, et al. Genetically Engineering Cell Membrane-Coated BTO Nanoparticles for MMP2-Activated Piezocatalysis-Immunotherapy. Adv Mater. 2023:e2300964.

[272] Nguyen VH, Kim HS, Ha JM, Hong Y, Choy HE, Min JJ. Genetically engineered Salmonella typhimurium as an imageable therapeutic probe for cancer. Cancer Res. 2010; 70(1): 18–23.

[273] Danino T, Prindle A, Kwong GA, Skalak M, Li H, Allen K, et al. Programmable probiotics for detection of cancer in urine. Sci Transl Med. 2015; 7(289): 289ra84.

[274] Chowdhury S, Castro S, Coker C, Hinchliffe TE, Arpaia N, Danino T. Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat Med. 2019; 25(7): 1057–1063.

[275] Hu Q, Wu M, Fang C, Cheng C, Zhao M, Fang W, et al. Engineering nanoparticle-coated bacteria as oral DNA vaccines for cancer immunotherapy. Nano Lett. 2015; 15(4): 2732–2739.

[276] Yi W, Xiao P, Liu X, Zhao Z, Sun X, Wang J, et al. Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry. Signal Transduct Target Ther. 2022; 7(1): 386.

[277] Xiao Y, Wang D, Luo B, Chen X, Yao Y, Song C, et al. In-situ synthesis of melanin in tumor with engineered probiotics for hyperbaric oxygen-synergized photothermal immunotherapy. Nano Today. 2022; 47: 101632.

[278] Chen J, Li T, Liang J, Huang Q, Huang JD, Ke Y, et al. Current status of intratumour microbiome in cancer and engineered exogenous microbiota as a promising therapeutic strategy. Biomed Pharmacother. 2022; 145: 112443.

[279] Roberts NJ, Zhang L, Janku F, Collins A, Bai RY, Staedtke V, et al. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci Transl Med. 2014; 6(249): 249ra111.

[280] Camarillo-Guerrero LF, Almeida A, Rangel-Pineros G. Finn RD, Lawley TD. Massive expansion of human gut bacteriophage diversity. Cell. 2021; 184(4): 1098–1109.e9.

[281] Cao B, Yang M, Mao C. Phage as a Genetically Modifiable Supramacromolecule in Chemistry, Materials and Medicine. Acc Chem Res. 2016; 49(6): 1111–1120.

[282] Petrov G, Dymova M, Richter V. Bacteriophage-Mediated Cancer Gene Therapy. Int J Mol Sci. 2022; 23(22): 14245.

[283] Jones KM, Karanam B, Jones-Triche J. Sandey M, Henderson HJ, Samant RS, et al. Phage Ligands for Identification of Mesenchymal-Like Breast Cancer Cells and Cancer-Associated Fibroblasts. Front Oncol. 2018; 8: 625.

[284] Pande J, Szewczyk MM, Grover AK. Phage display: concept, innovations, applications and future. Biotechnol Adv. 2010; 28(6): 849–858.

[285] Saw PE, Song EW. Phage display screening of therapeutic peptide for cancer targeting and therapy. Protein Cell. 2019; 10(11): 787–807.

[286] Bhasin A, Drago NP, Majumdar S, Sanders EC, Weiss GA, Penner RM. Viruses Masquerading as Antibodies in Biosensors: The Development of the Virus BioResistor. Acc Chem Res. 2020; 53(10): 2384–2394.

[287] Li C, Li J, Xu Y, Zhan Y, Li Y, Song T, et al. Application of Phage-Displayed Peptides in Tumor Imaging Diagnosis and Targeting Therapy. Int J Pept Res Ther. 2021; 27(1): 587–595.

[288] Li Y, Qu X, Cao B, Yang T, Bao Q, Yue H, et al. Selectively Suppressing Tumor Angiogenesis for Targeted Breast Cancer Therapy by Genetically Engineered Phage. Adv Mater. 2020; 32(29): e2001260.

[289] Gurung S, Khan F, Gunassekaran GR, Yoo JD, Poongkavithai Vadevoo SM, Permpoon U, et al. Phage display-identified PD-L1-binding peptides reinvigorate T-cell activity and inhibit tumor progression. Biomaterials. 2020; 247: 119984.

[290] Wang J, Lamolinara A, Conti L, Giangrossi M, Cui L, Morelli MB, et al. HER2-Displaying M13 Bacteriophages induce Therapeutic Immunity against Breast Cancer. Cancers (Basel). 2022; 14(16): 4054.

[291] Sindhwani S, Syed AM, Ngai J, Kingston BR, Maiorino L, Rothschild J, et al. The entry of nanoparticles into solid tumours. Nat Mater. 2020; 19(5): 566–575.

[292] de la Zerda A, Bodapati S, Teed R, May SY, Tabakman SM, Liu Z, et al. Family of enhanced photoacoustic imaging agents for high-sensitivity and multiplexing studies in living mice. ACS Nano. 2012; 6(6): 4694–4701.

[293] Li J, Rao J, Pu K. Recent progress on semiconducting polymer nanoparticles for molecular imaging and cancer phototherapy. Biomaterials. 2018; 155: 217–235.

[294] Wu X, Ye J, DeLaitsch AT, Rashidijahanabad Z, Lang S, Kakeshpour T, et al. Chemoenzymatic Synthesis of 9NHAc-GD2 Antigen to Overcome the Hydrolytic Instability of O-Acetylated-GD2 for Anticancer Conjugate Vaccine Development. Angew Chem Int Ed Engl. 2021; 60(45): 24179–24188.

[295] Yata T, Lee EL, Suwan K, Syed N, Asavarut P, Hajitou A. Modulation of extracellular matrix in cancer is associated with enhanced tumor cell targeting by bacteriophage vectors. Mol Cancer. 2015; 14: 110.

[296] Xiao L, Ma N, He H, Li J, Cheng S, Yang Q, et al. Development of a novel drug targeting delivery system for cervical cancer therapy. Nanotechnology. 2019; 30(7): 075604.

[297] Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: A new era of cancer treatment at dawn. Cancer Science. 2016; 107(10): 1373–1379.

[298] Shalhout SZ, Miller DM, Emerick KS, Kaufman HL. Therapy with oncolytic viruses: progress and challenges. Nat Rev Clin Oncol. 2023; 20(3): 160–177.

[299] Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014; 2(4): 295–300.

[300] Hennessy ML, Bommareddy PK, Boland G, Kaufman HL. Oncolytic Immunotherapy. Surg Oncol Clin N Am. 2019; 28(3): 419–430.

[301] Conry RM, Westbrook B, McKee S, Norwood TG. Talimogene laherparepvec: First in class oncolytic virotherapy. Hum Vaccin Immunother. 2018; 14(4): 839–846.

[302] Soliman H, Hogue D, Han H, Mooney B, Costa R, Lee MC, et al. Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial. Nat Med. 2023; 29(2): 450–457.

[303] Garber K. China approves world’s first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst. 2006; 98(5): 298–300.

[304] Doniņa S, Strēle I, Proboka G, Auziņš J, Alberts P, Jonsson B, et al. Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study. Melanoma Res. 2015; 25(5): 421–426.

[305] Todo T, Ito H, Ino Y, Ohtsu H, Ota Y, Shibahara J, et al. Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: a phase 2 trial. Nat Med. 2022; 28(8): 1630–1639.

[306] Bommareddy PK, Patel A, Hossain S, Kaufman HL. Talimogene Laherparepvec (T-VEC) and Other Oncolytic Viruses for the Treatment of Melanoma. Am J Clin Dermatol. 2017; 18(1): 1–15.

[307] Ylosmaki E, Cerullo V. Design and application of oncolytic viruses for cancer immunotherapy. Curr Opin Biotechnol. 2020; 65: 25–36.

[308] Russell L, Swanner J, Jaime-Ramirez AC. Wang Y, Sprague A, Banasavadi-Siddegowda Y. et al. PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance. Nat Commun. 2018; 9(1): 5006.

[309] Watanabe K, Luo Y, Da T, Guedan S, Ruella M, Scholler J, et al. Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. JCI Insight. 2018; 3(7): e99573.

[310] Fares J, Ahmed AU, Ulasov IV, Sonabend AM, Miska J, Lee-Chang C. et al. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial. Lancet Oncol. 2021; 22(8): 1103–1114.

[311] Saari H, Turunen T, Lõhmus A, Turunen M, Jalasvuori M, Butcher SJ, et al. Extracellular vesicles provide a capsid-free vector for oncolytic adenoviral DNA delivery. J Extracell Vesicles. 2020; 9(1): 1747206.

[312] Sun M, Yang S, Huang H, Gao P, Pan S, Cheng Z, et al. Boarding Oncolytic Viruses onto Tumor-Homing Bacterium-Vessels for Augmented Cancer Immunotherapy. Nano Lett. 2022; 22(12): 5055–5064.

[313] Howard FHN, Al-Janabi H. Patel P, Cox K, Smith E, Vadakekolathu J, et al. Nanobugs as Drugs: Bacterial Derived Nanomagnets Enhance Tumor Targeting and Oncolytic Activity of HSV-1 Virus. Small. 2022; 18(13): e2104763.

[314] Bommareddy PK, Aspromonte S, Zloza A, Rabkin SD, Kaufman HL. MEK inhibition enhances oncolytic virus immunotherapy through increased tumor cell killing and T cell activation. Sci Transl Med. 2018; 10(471): eaau0417.

[315] Saha D, Martuza RL, Rabkin SD. Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade. Cancer Cell. 2017; 32(2): 253–267 e5.

[316] Bourgeois-Daigneault MC, Roy DG, Aitken AS, El Sayes N, Martin NT, Varette O, et al. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci Transl Med. 2018; 10(422): eaao1641.

[317] Chen Z, Xie H, Hu M, Huang T, Hu Y, Sang N, et al. Recent progress in treatment of hepatocellular carcinoma. Am J Cancer Res. 2020; 10(9): 2993–3036.

[318] Muthana M, Rodrigues S, Chen YY, Welford A, Hughes R, Tazzyman S, et al. Macrophage delivery of an oncolytic virus abolishes tumor regrowth and metastasis after chemotherapy or irradiation. Cancer Res. 2013; 73(2): 490–495.

[319] Villalona-Calero MA, Lam E, Otterson GA, Zhao W, Timmons M, Subramaniam D, et al. Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non-small cell lung cancer patients with KRAS-activated tumors. Cancer. 2016; 122(6): 875–883.

[320] Liu Z, Ravindranathan R, Kalinski P, Guo ZS, Bartlett DL. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat Commun. 2017; 8: 14754.

[321] Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017; 170(6): 1109–1119.

[322] Puzanov I, Milhem MM, Minor D, Hamid O, Li A, Chen L, et al. Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma. J Clin Oncol. 2016; 34(22): 2619–2626.

[323] Franklin C, Livingstone E, Roesch A, Schilling B, Schadendorf D. Immunotherapy in melanoma: Recent advances and future directions. Ejso. 2017; 43(3): 604–611.

[324] Harrington K, Freeman DJ, Kelly B, Harper J, Soria JC. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov. 2019; 18(9): 689–706.

[325] Wing A, Fajardo CA, Posey AD, Jr., Shaw C, Da T, Young RM, et al. Improving CART-Cell Therapy of Solid Tumors with Oncolytic Virus-Driven Production of a Bispecific T-cell Engager. Cancer Immunol Res. 2018; 6(5): 605–616.

[326] Shi W, Wang Y, Xu C, Li Y, Ge S, Bai B, et al. Multilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer. Nat Commun. 2023; 14(1): 835.

[327] Narunsky-Haziza L, Sepich-Poore GD. Livyatan I, Asraf O, Martino C, Nejman D, et al. Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell. 2022; 185(20): 3789–3806 e17.

[328] Nougayrede JP, Homburg S, Taieb F, Boury M, Brzuszkiewicz E, Gottschalk G, et al. Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science. 2006; 313(5788): 848–851.

[329] Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J, Gamliel M, et al. Binding of the Fap2 Protein of Fusobacterium nucleatum to Human Inhibitory Receptor TIGIT Protects Tumors from Immune Cell Attack. Immunity. 2015; 42(2): 344–355.

RIGHTS & PERMISSIONS

2024 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.