Sex-biased intratumoral microbiome influences tumor molecular and immune landscape and disease outcomes
- Cell Rep Med. 2026 May 19;7(5):102757. doi: 10.1016/j.xcrm.2026.102757.
- 1. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
- 2. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA; Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt.
- 3. Caris Life Sciences, Irving, TX, USA.
- 4. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
- 5. Department of Otolaryngology - Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
- 6. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
- 7. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.
- 8. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. Electronic address: [email protected].
The intratumoral microbiome is increasingly recognized as a regulator of Cancer biology, yet sex-specific patterns and their relevance to Cancer disparities remain poorly understood. We perform a multi-kingdom analysis of more than 5,000 tumors from seven datasets to identify sex-differential microbial taxa across aerodigestive and gastrointestinal cancers. We identify and validate 22 taxa with consistent sex-biased abundance, including in real-world cohort. These microbes show cancer-type- and microbe-specific associations with tumor transcriptomes, oncogenic pathways, and immune cell infiltration. Female-enriched microbes are linked to increased estrogen signaling and interferon responses, whereas male-enriched taxa show opposing patterns. In gastric Cancer, intratumoral Epstein-Barr virus is enriched in males and associated with higher CD8+ T cell infiltration and improved survival. Functional co-culture experiments demonstrate that sex-biased microbes modulate chemotherapy sensitivity. Together, these findings reveal a sex-biased intratumoral microbiome axis that shapes tumor phenotypes and disease outcomes, highlighting opportunities for microbiota-guided, sex-aware approaches in oncology.