An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV⁻) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3⁺ and CD8⁺ T cell microenvironments in precancer (mostly CD3⁺, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV⁻ HNSC after anti–PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.

非整倍体免疫悖论包括体细胞拷贝数改变 (SCNA)，在实验性癌前系统中释放细胞毒性反应，同时与人类肿瘤，尤其是头颈癌 (HNSC) 中的免疫抑制和细胞毒性细胞耗竭相关。^{我们提供来自患者样本和细胞系的证据，即染色体剂量的改变有助于人乳头瘤病毒阴性 (HPV -} ) 头颈部肿瘤发生过程中的免疫冷热转换。总体 SCNA（非整倍性）水平与癌前病变中 CD3 ⁺和 CD8 ⁺ T 细胞微环境的增加（主要是 CD3 ⁺，与三体性和非整倍性有关），但与 T 细胞缺陷型肿瘤有关。9p21.3 缺失的早期病变与TP53突变肿瘤中细胞毒性 T 细胞浸润的消耗有关；和非整倍性与增加的 NK 细胞浸润有关。口腔癌中细胞毒性 T 细胞和免疫评分下降的最强驱动因素是 9p 臂水平下降，促进了关键的 IFN-γ 相关趋化因子（例如，CXCL9）和通路基因的显着下降。染色体 9p21.3 缺失主要导致细胞固有的衰老抑制，但整个臂的缺失对于降低细胞因子、JAK-STAT 和 Hallmark NF-κB 通路的水平是必要的。最后，9p arm-level loss 和JAK2 - PD-L1共缺失（9p24）是抗 PD-1 治疗后复发性 HPV ^{- HNSC 存活率低的预测标志物；}可能被此处观察到的独立非整倍体诱导的免疫冷微环境放大。我们假设 9p21.3 手臂丢失扩展和上位相互作用使口腔癌前细胞获得了克服前免疫原性非整倍体检查点、转化和入侵的特性。这些发现实现了独特的 HNSC 拦截和精确治疗方法，这些概念可能适用于其他 CN 驱动的肿瘤、免疫或非整倍体疾病以及免疫疗法。