Oral Fungal Infection Impacts Epithelial Innate Immunity to Promote Local and Distal Squamous Cell Carcinoma Progression

Abstract Fungi have been detected within human tumors and shown to support tumor progression. A better understanding of how intratumoral fungi evade innate immunity, remodel the tumor microenvironment (TME), and promote tumorigenesis may provide insights into cancer pathogenesis and therapeutic strategies. Here, we showed that aggressive human head and neck squamous cell carcinomas (HNSCCs) harbor an elevated fungal burden, including the environmental fungus Cladosporium cladosporioides, and are infiltrated by IL1B-high neutrophils with impaired reactive oxygen species (ROS) production and phagocytosis, as well as IL1B-high macrophages. In a mouse model in which Ikka ablation drives tumorigenesis through EGFR and STAT3 activation, oral C. cladosporioides infection recapitulated key features of the human HNSCC TME, elevated serum IL-1β and IL-17A levels, and promoted both oral and skin SCC development. Oral fungal infection also increased the acidic metabolites uric acid and lactate in the TME. These metabolites enhanced C. cladosporioides-induced IL-1β production while reducing ROS production in neutrophils, thereby impairing fungal clearance. Mechanistically, C. cladosporioides, IL-1β, and IL-17A activated STAT3 and cyclin D1 signaling in SCC cells. Epithelial Stat3 deletion abrogated both Ikka loss-driven and fungus-enhanced oral and skin carcinogenesis, reduced macrophage accumulation, restored normal oral neutrophil phenotypes, and cleared oral fungal infection. Furthermore, IL-1β induced by C. cladosporioides inoculation drove systemic inflammation that promoted skin SCC via an IL-1β/IL-1R feedback loop involving neutrophils and macrophages. Together, these findings identify a fungus-driven immunosuppressive circuit in which tumor-derived acidic metabolites impair antifungal immunity, thereby promoting both local and distal SCC progression.

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Publication Details

Journal
Cancer Research
Published
2026-09-10
DOI
https://doi.org/10.1158/0008-5472.can-26-0070
Primary Topic
Immune cells in cancer
Type
article
Field-Weighted Citation Impact
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article

Oral Fungal Infection Impacts Epithelial Innate Immunity to Promote Local and Distal Squamous Cell Carcinoma Progression

Bao Tran, Xiaolin Wu, Colm Ó’hUigín, Xia Xu et al.
Cancer Research
Immune cells in cancer
article

Oral Fungal Infection Impacts Epithelial Innate Immunity to Promote Local and Distal Squamous Cell Carcinoma Progression

Bao Tran, Xiaolin Wu, Colm Ó’hUigín, Xia Xu, Elise M. N. Ferré, Debra Tross, Michail S. Lionakis, Gongping Shi, King C. Chan, Yinling Hu, Yongmei Zhao, Na‐Young Song, Þorkell Andrésson, Chengfei Jiang, Feng Zhu, Seyedmojtaba Seyedmousavi, Jami Willette‐Brown, Giorgio Trinchieri, Timothy Gower, Jonathan H. Badger, Peilin Zhang, Sayantan Banerjee, Zhonghe Sun, Rodrigo Xavier das Neves, Xin Li, Amit Kumar. Singh
article en

Abstract

Abstract Fungi have been detected within human tumors and shown to support tumor progression. A better understanding of how intratumoral fungi evade innate immunity, remodel the tumor microenvironment (TME), and promote tumorigenesis may provide insights into cancer pathogenesis and therapeutic strategies. Here, we showed that aggressive human head and neck squamous cell carcinomas (HNSCCs) harbor an elevated fungal burden, including the environmental fungus Cladosporium cladosporioides, and are infiltrated by IL1B-high neutrophils with impaired reactive oxygen species (ROS) production and phagocytosis, as well as IL1B-high macrophages. In a mouse model in which Ikka ablation drives tumorigenesis through EGFR and STAT3 activation, oral C. cladosporioides infection recapitulated key features of the human HNSCC TME, elevated serum IL-1β and IL-17A levels, and promoted both oral and skin SCC development. Oral fungal infection also increased the acidic metabolites uric acid and lactate in the TME. These metabolites enhanced C. cladosporioides-induced IL-1β production while reducing ROS production in neutrophils, thereby impairing fungal clearance. Mechanistically, C. cladosporioides, IL-1β, and IL-17A activated STAT3 and cyclin D1 signaling in SCC cells. Epithelial Stat3 deletion abrogated both Ikka loss-driven and fungus-enhanced oral and skin carcinogenesis, reduced macrophage accumulation, restored normal oral neutrophil phenotypes, and cleared oral fungal infection. Furthermore, IL-1β induced by C. cladosporioides inoculation drove systemic inflammation that promoted skin SCC via an IL-1β/IL-1R feedback loop involving neutrophils and macrophages. Together, these findings identify a fungus-driven immunosuppressive circuit in which tumor-derived acidic metabolites impair antifungal immunity, thereby promoting both local and distal SCC progression.

Cancer Research
Leidos (United States) (US), National Institutes of Health (US), National Health Research Institutes (TW), UPMC Hillman Cancer Center (US), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (MY), National Institute of Allergy and Infectious Diseases (US), National Cancer Institute (US), CS Diagnostics (DE), National Institutes of Health Clinical Center (US), National Cancer Research Institute (GB)
Openalex Percentile: Top 17%
Immune cells in cancer
DOISourceOpenAlex
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