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Divergent Genomic Trajectories Specify Distinct Tumor Ecotypes and Reveal Targetable Immune Evasion in Oral Carcinogenesis

This article is a preprint and has not been certified by peer review.

Authors

    Yuanfu Zhang,  
    Yuanfu Zhang
    Rong-quan Xiao,  
    Rong-quan Xiao
    Yingying Feng,  
    Yingying Feng
    Yi Ren,  
    Yi Ren
    Hongtao Jin,  
    Hongtao Jin
    Jiayi Ye,  
    Jiayi Ye
    • Peking University School and Hospital of Stomatology
    Tianxin Wang,   Zheng Zhang,  
    Zheng Zhang
    Jianming Tang,  
    Jianming Tang
    Hongliang Xie,  
    Hongliang Xie
    Chenchen Ma,  
    Chenchen Ma
    Jiaxuan Li,  
    Jiaxuan Li
    Ran Zhang,  
    Ran Zhang
    • Peking University School and Hospital of Stomatology
    Guoquan Zhang,  
    Guoquan Zhang
    Shimin Shuai
    Shimin Shuai
Categories
Genetics & Genomics
Keywords
Oral squamous cell carcinoma; head and neck cancer; oral leukoplakia; tumor microenvironment; cancer evolution; cancer multi-omics; cancer-associated fibroblasts; immunotherapy resistance; cancer subtyping; TNFRSF12A

Abstract

Oral squamous cell carcinoma, the predominant subtype of head and neck cancer, exhibits limited immunotherapy efficacy, yet the biological basis remains unclear. Through integrative multi-omics analysis spanning the full carcinogenesis continuum, we identify two fundamental tumor ecotypes: Infiltrated-Exhausted (IE) with adaptive T cell suppression, and Fibrotic-Excluded (FE) with a stromal barrier physically excluding lymphocytes. IE tumors follow a linear, hypermutation-driven trajectory enriched for NOTCH1/CASP8 mutations, while FE tumors emerge via branched, chromosomally unstable evolution with EGFR alterations. These divergent programs are already detectable at the precancer stage. We identify the TWEAK-TNFRSF12A signaling circuit involving SPP1+ macrophages, partial-EMT tumor cells and COL1A1+ fibroblasts as the architectural keystone of the FE niche. Targeting TNFRSF12A in vivo dismantles the exclusion barrier, converting cold tumors to an inflamed state and sensitizing them to anti-PD-1 therapy. This study links genomic evolution to microenvironmental fate and provides an ecotype-guided framework for precision immunotherapy.

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DOI:

https://doi.org/10.65215/LTSpreprints.2026.03.28.000168

Submission ID:

168

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Posted

2026-03-28

How to Cite

Zhang, Y., Xiao, R.- quan, Feng, Y., Ren, Y., Jin, H., Ye, J., Wang, T., Zhang, Z., Tang, J., Xie, H., Ma, C., Li, J., Zhang, R., Zhang, G., & Shuai, S. (2026). Divergent Genomic Trajectories Specify Distinct Tumor Ecotypes and Reveal Targetable Immune Evasion in Oral Carcinogenesis. LangTaoSha Preprint Server. https://doi.org/10.65215/LTSpreprints.2026.03.28.000168

Declaration of Competing Interests

Details of all competing interests to be disclosed are as follows:

The patent application related to the article was submitted to the State Intellectual Property Office of China (Application No.: 202511878789.5) for YZ, GZ, and SS.

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The copyright holder for this preprint is the author/funder.

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.