Tumor microbial burden drives immune responses through regulation of Interferon signaling
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 (CRC) and gastric (STAD) cancers. High ITMB CRC leads to interferon regulation and is associated with improved outcomes in advanced disease. Single-cell sequencing revealed induction of interferon-related genes (IRGs) within microbes-containing human CRC. GI-luminal mismatch repair deficiency (MMRd) tumors had higher ITMB than proficient tumors (MMRp). In a rectal MMRd cohort with 100% remission after immune checkpoint blockade (ICB), tumor microbes and microbes-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 between ITMB, host defense, and immunogenicity which seems key to determine therapy responses.
Authors
- Erika Ruíz‐García (ORCID: https://orcid.org/0000-0002-0446-123X)
- Scott Kopetz (ORCID: https://orcid.org/0000-0001-9647-3416)
- Jared K. Burks (ORCID: https://orcid.org/0000-0002-6173-9074)
- Vidhi Chandra (ORCID: https://orcid.org/0000-0003-3642-2144)
- Amir Hossein Mohseni (ORCID: https://orcid.org/0000-0003-0320-9523)
- Erika Y. Faraoni (ORCID: https://orcid.org/0000-0003-0731-2122)
- Daniel Carvajal (ORCID: https://orcid.org/0000-0003-1742-729X)
- Fuduan Peng (ORCID: https://orcid.org/0000-0003-4068-530X)
- Andrea Cercek (ORCID: https://orcid.org/0000-0002-5054-8192)
- Edith A. Fernández-Figueroa (ORCID: https://orcid.org/0000-0002-5159-8300)
- Hajar Rajaei (ORCID: https://orcid.org/0000-0002-8803-8841)
- Barbara Mino (ORCID: https://orcid.org/0000-0001-9217-8719)
- Sedigheh Taghinezhad‐S (ORCID: https://orcid.org/0000-0002-4497-4427)
- Florencia McAllister (ORCID: https://orcid.org/0000-0002-9915-0943)
- James R. White (ORCID: https://orcid.org/0000-0002-7535-9179)
- Luis Alberto Diaz (ORCID: https://orcid.org/0000-0002-7079-8914)
- Linghua Wang (ORCID: https://orcid.org/0000-0001-9380-0266)
- Seyda Baydogan (ORCID: https://orcid.org/0000-0002-9455-640X)
- Steven B. Maron (ORCID: https://orcid.org/0000-0002-8794-130X)
- Yuehui Zhao (ORCID: https://orcid.org/0000-0002-9496-0023)
- Nicholas E. Navin (ORCID: https://orcid.org/0000-0002-2106-8624)
- Erick Riquelme (ORCID: https://orcid.org/0000-0002-2696-7995)
- Mitesh Patel (ORCID: https://orcid.org/0000-0001-6724-9183)
- Javier A. Gomez (ORCID: https://orcid.org/0000-0002-6579-744X)
- Dhwani N. Rupani (ORCID: https://orcid.org/0000-0003-2325-4057)
- Thais Fernanda Bartelli (ORCID: https://orcid.org/0000-0002-1373-0112)
- Olivereen Le Roux (ORCID: https://orcid.org/0000-0003-1882-879X)
- Jeong‐Hoon Jang (ORCID: https://orcid.org/0000-0002-5925-6524)
- Haoyue Liu (ORCID: https://orcid.org/0000-0003-0498-2796)
- Li Li (ORCID: https://orcid.org/0009-0003-4636-9487)
- Virginia Tahan (ORCID: https://orcid.org/0009-0006-8326-3536)
- Fernando Jimenez-Arancon
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Universidad del Desarrollo (CL)
- The University of Texas MD Anderson Cancer Center (US)
- Seoul National University (KR)
- Pontificia Universidad Católica de Chile (CL)
- Clínica Alemana (CL)
- New Generation University College (ET)
- National Institute of Genomic Medicine (MX)
- Instituto Nacional de Cancerología (MX)
- Resphera Biosciences (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-06-26
- DOI
- https://doi.org/10.1158/2159-8290.cd-24-1908
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00