<p>The initiation and progression of cancer are driven by the dynamic interplay between somatic mutations and the tumor microenvironment. Identifying core cell populations driving malignant transformation and understanding the intercellular interactions within the tumor microenvironment are, therefore, crucial for early diagnosis and effective treatment. Here, we construct a spatiotemporal atlas of oral squamous cell carcinoma (OSCC) progression by integrating multi-omics approaches. Our analysis reveals that the critical driver gene PLAU activates the TGF-β pathway via ITGB1, thereby promoting the conversion of fibroblasts into the COL11A1⁺ fibroblast (COL11A1⁺ Fib). These specialized fibroblasts remodel the extracellular matrix (ECM), collectively establishing an immunosuppressive niche composed of malignant epithelial cells, COL11A1⁺ Fib, and regulatory T cells (Tregs). Importantly, targeting COL11A1⁺ Fib alleviates this immunosuppressive niche and curbs OSCC progression. Our findings underscore the potential of COL11A1⁺ Fib as a predictive biomarker, especially in combination with immunotherapy. Collectively, this work demonstrates that the PLAU-ITGB1-TGF-β axis drives the formation of an Epi-COL11A1⁺ Fib-Treg immunosuppressive niche that fuels OSCC malignancy.</p><p></p>