Peer-reviewedCC BY-NC-ND 4.0Cancer Discovery
Tumor Microbial Burden Drives Immune Responses through Regulation of Interferon Signaling
17 affiliations
- 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 2Tumor Ecosystems Center, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 3Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 4College of Pharmacy, Daegu Catholic University, Gyeongsan-si, South Korea.
- 5Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 6Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 7Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 8Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
- 9Clínica Alemana, Facultad de Medicina, Universidad del Desarrollo, Santiago, Chile.
- 10Departamento de Tumores de Tubo Digestivo, Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, Ciudad de México, Mexico.
- 11Núcleo B de Innovación en Medicina de Precisión, Instituto Nacional de Medicina Genómica, Ciudad de México, Mexico.
- 12Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 13Respiratory Diseases Department, Faculty of Medicine, Pontifical Catholic University of Chile, Santiago, Chile.
- 14Resphera Biosciences LLC, Baltimore, Maryland.
- 15Institute for Data Science in Oncology (IDSO), Houston, Texas.
- 16James P. Allison Institute (JPAI), The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 17Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Abstract
Tumor microbes are increasingly recognized for modulating tumor behavior and therapy responses. Intratumoral microbial burden (ITMB) analysis across cancers revealed regulation of immune pathways and activated mast cells, mostly in colorectal and gastric cancers. High-ITMB colorectal cancer leads to interferon (IFN) regulation and is associated with improved outcomes in advanced disease. Single-cell sequencing revealed induction of IFN-related genes (IRG) within microbe-containing human colorectal cancer. Gastrointestinal-luminal mismatch repair–deficient (MMRd) tumors had higher ITMB than proficient tumors. In a rectal MMRd cohort with 100% remission after immune checkpoint blockade (ICB), tumor microbes and microbe-containing mast cells increased. In ICB-sensitive syngeneic murine MMRd tumor models, local tumor microbial depletion impaired ICB efficacy while downregulating IFN signaling. Forced upregulation of IRGs in ADAR1-deficient cancer cells restored immunotherapy responses during microbial ablation. These data highlight dynamic interplay among ITMB, host defense, and immunogenicity, which seems key to determine therapy responses.
Significance:: The ITMB is linked to transcriptional and immune functional changes that seem to determine tumor sensitivity to immunotherapy. These findings highlight the key role of tumor-resident microbes in shaping the tumor ecosystem, which could be targeted to modulate therapy responses.
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BibTeX
@article{liu2026tumor,
title = {{Tumor Microbial Burden Drives Immune Responses through Regulation of Interferon Signaling}},
author = {Haoyue Liu and Jeong-Hoon Jang and Fuduan Peng and Hajar Rajaei and Vidhi Chandra and Le Li and Dhwani N. Rupani and Sedigheh Taghinezhadsaroukalaei and Yuehui Zhao and Erika Y. Faraoni and Thais F. Bartelli and Olivereen Le Roux and Virginia Tahan and Fernando Jimenez-Arancon and Seyda Baydogan and Amir Hossein Mohseni and Javier A. Gomez and Mitesh Patel and Jared K. Burks and Barbara Miño Galvez and Daniel E. Carvajal-Hausdorf and Erika Ruiz-García and Edith A. Fernandez-Figueroa and Scott Kopetz and Steven B. Maron and Andrea Cercek and Erick M. Riquelme and Nicholas E. Navin and James Robert White and Linghua Wang and Luis A. Diaz and Florencia McAllister},
journal = {Cancer Discovery},
year = {2026},
month = jun,
doi = {10.1158/2159-8290.cd-24-1908},
url = {https://doi.org/10.1158/2159-8290.cd-24-1908},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Tumor Microbial Burden Drives Immune Responses through Regulation of Interferon Signaling
AU - Haoyue Liu
AU - Jeong-Hoon Jang
AU - Fuduan Peng
AU - Hajar Rajaei
AU - Vidhi Chandra
AU - Le Li
AU - Dhwani N. Rupani
AU - Sedigheh Taghinezhadsaroukalaei
AU - Yuehui Zhao
AU - Erika Y. Faraoni
AU - Thais F. Bartelli
AU - Olivereen Le Roux
AU - Virginia Tahan
AU - Fernando Jimenez-Arancon
AU - Seyda Baydogan
AU - Amir Hossein Mohseni
AU - Javier A. Gomez
AU - Mitesh Patel
AU - Jared K. Burks
AU - Barbara Miño Galvez
AU - Daniel E. Carvajal-Hausdorf
AU - Erika Ruiz-García
AU - Edith A. Fernandez-Figueroa
AU - Scott Kopetz
AU - Steven B. Maron
AU - Andrea Cercek
AU - Erick M. Riquelme
AU - Nicholas E. Navin
AU - James Robert White
AU - Linghua Wang
AU - Luis A. Diaz
AU - Florencia McAllister
PY - 2026
DA - 2026/06/26
JO - Cancer Discovery
DO - 10.1158/2159-8290.cd-24-1908
UR - https://doi.org/10.1158/2159-8290.cd-24-1908
AB - Tumor microbes are increasingly recognized for modulating tumor behavior and therapy responses. Intratumoral microbial burden (ITMB) analysis across cancers revealed regulation of immune pathways and activated mast cells, mostly in colorectal and gastric cancers. High-ITMB colorectal cancer leads to interferon (IFN) regulation and is associated with improved outcomes in advanced disease. Single-cell sequencing revealed induction of IFN-related genes (IRG) within microbe-containing human colorectal cancer. Gastrointestinal-luminal mismatch repair–deficient (MMRd) tumors had higher ITMB than proficient tumors. In a rectal MMRd cohort with 100% remission after immune checkpoint blockade (ICB), tumor microbes and microbe-containing mast cells increased. In ICB-sensitive syngeneic murine MMRd tumor models, local tumor microbial depletion impaired ICB efficacy while downregulating IFN signaling. Forced upregulation of IRGs in ADAR1-deficient cancer cells restored immunotherapy responses during microbial ablation. These data highlight dynamic interplay among ITMB, host defense, and immunogenicity, which seems key to determine therapy responses. Significance:: The ITMB is linked to transcriptional and immune functional changes that seem to determine tumor sensitivity to immunotherapy. These findings highlight the key role of tumor-resident microbes in shaping the tumor ecosystem, which could be targeted to modulate therapy responses.
SN - 2159-8274
SN - 2159-8290
ER -