Understanding molecular changes during tumor initiation and progression is crucial for cancer prevention and treatment. Here, we generated a comprehensive atlas of 232,655 single-cell transcriptomes, 58,800 single-cell epigenomes, spatial transcriptomes, and whole exome profiling derived from 15 oral cancer patients, consisting of matched human oral mucosal biopsies from tumors, precancerous lesions, and adjacent normal tissues. Our analysis revealed two distinct transition programs from normal epithelial to aneuploid cells, including stressing and cycling branches separately enriched in precancerous and tumor samples. Remarkably, we observed distinct microenvironment ecotypes between tumor, precancerous, and adjacent normal samples. Exhausted and regulatory T-cells were highly enriched in tumors, along with a reduction in CD1C-positive dendritic cells. Interestingly, we identified a subset of exhausted CD8 T-cells within the tumor that exhibited resilient cytotoxic activity and higher levels of effector cytokines, which were potentially induced by BATF activity. Finally, integrated analysis with WES data established strong links between microenvironment ecotype evolution and driver mutations. Collectively, our study portrays a comprehensive landscape during oral tumor formation and unveils the links between malignant cell formation and microenvironment evolution. Our findings also offer valuable resources for targeting immune cell activation and infiltration in the context of oral cancer.