IL-1α Expands SLC2A1highSPP1highIFNlow Myeloid Cells to Drive Immune Escape and Malignant Transformation of Pre-cancers.

Authors

Hülya Taner, Wang Gong, Emily A Lanzel, Kala Chand Debnath, Felipe Nör, Kohei Okuyama, Yuesong Wu, Charisse A Ursin, Shajedul Islam, Xin Hu, Yumin He, Zackary R Fitzsimonds, Zaiye Li, Jung M Kuczura, Sashider Rajesh, Andriana Manousidaki, Shuo Feng, Miki Lee, Shadmehr Demehri, Haitao Wen, Andrew G Sikora, Mark S Chambers, Jeffrey N Myers, Peter J Polverini, Jacques E Nör, Simon Young, Thomas D Wang, Jianwen Que, Jian Hu, Yuying Xie, James J Moon, Yu Leo Lei

Published in

Cancer research. Jul 14, 2026. Epub Jul 14, 2026.

Abstract

Head and neck squamous cell carcinomas (HNSCC) are preceded by potentially malignant precursor lesions, highlighting the need for strategies to discern which precancerous lesions harbor a high risk for malignant transformation. Here, we developed a unique genetically engineered mouse model (GEMM) by inducing oral epithelial cell-specific amplification of Sox2, which recapitulates the malignant transformation of epithelial dysplasia to HNSCC with high histologic and phenotypic resemblance to human tumors. SOX2 promoted the release of IL-1α and CCL2, expanding inflammatory monocytes. The recruited myeloid cells exhibited a distinct, early, high-risk signature of high levels of IL-1α, SLC2A1, SPP1, and low levels of type-I interferon (IFN-I) targets, and intralesional SLC2A1high myeloid cells were more suppressive than their SLC2A1low counterparts. Brief priming of myeloid cells with IL-1α desensitized them to STING agonists and enhanced the suppressive effects of myeloid-derived suppressor cells on T-cell activation. Mechanistically, IL-1 activation repressed the expression of DHHC3/7 enzymes that palmitoylate STING. Early blockade of IL-1 signaling using pharmacologic and genetic approaches similarly reduced the most suppressive subsets of myeloid cells, promoted immune surveillance against the progression of epithelial dysplasia, and extended survival. This work establishes a central high-risk myeloid cell transcriptomic program, characterized by elevated levels of IL-1α, SLC2A1, and SPP1, that leads to irreversible immune escape upon transformation of precancerous epithelial lesions.

PMID:
42446924
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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