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