Significance

We report somatic copy-number alterations (SCNAs) that contribute to an immune microenvironment switch during human papillomavirus-negative head and neck cancer (HNSC) development. Specific and nonspecific SCNA levels were examined in a large prospective oral precancer (188 patients) cohort, 2 HNSC (343, 196 patients) cohorts, and 32 cell lines. Chromosome 9p21.3 loss in precursor lesions, the genomic driver of malignant transition, was enhanced by cumulative 9p-arm gene-dosage decreases, cell-intrinsic senescence suppression, and extrinsic decreases in chemokine, cytokine, and NF-κB pathways. Furthermore, 9p-arm loss and JAK2–PD-L1 codeletion were associated with PD-1 inhibitor resistance. These data reveal an oncogenic immune paradox, aneuploid checkpoint to neoplastic transformation, and immune interception and therapeutic strategies for HPV⁻ HNSC and possibly other CN-driven tumors or diseases.