HPV相关咽喉癌（HPVOPC）的肿瘤突变负担相对较低。阐明其他肿瘤改变（如DNA甲基化改变、可变剪接事件（ASE）和拷贝数变异（CNV））的相对贡献，可能深入了解该疾病的致癌机制。我们对46个初发的HPVOPC肿瘤和25个无癌变的对照进行了多类肿瘤改变的网络传播分析，并用TCGA数据验证了我们的发现。我们发现差异基因表达网络与所有改变类别存在显著重叠，其中与甲基化的关联最高，与CNV的关联最低。G蛋白偶联受体（GPCR）通路的基因簇也存在显著重叠。HPV16-人类蛋白相互作用分析发现了一个由免疫介导的GPCR信号定义的富集簇，其中包括CXCR3细胞因子CXCL9、CXCL10和CXCL11。在初发HPVOPC中发现了CXCR3的表达，并且单细胞RNA测序分析表明CXCR3配体在M2巨噬细胞中高度表达。体内模型实验表明，在免疫缺陷小鼠中CXCR3受体的拮抗能减缓肿瘤生长，但在免疫功能完整的小鼠中没有此效应，这表明CXCR3轴循环因素可能通过内源的方式驱动肿瘤增殖，但其效应受到完整的免疫系统的调控。总之，甲基化、ASE和SNV改变与HPVOPC的网络基因表达变化高度相关，提示ASE和甲基化改变在推动致癌表型方面起着重要作用。网络分析鉴定了GPCR网络，特别是CXCR3趋化因子轴，作为调节肿瘤免疫相互作用的调制因子，既可能对初发肿瘤具有增殖效应，也可能在免疫监视中发挥作用；然而，应谨慎使用CXCR3抑制剂，因为这些药物可能同时抑制和刺激肿瘤生长，考虑到该细胞因子轴的对立效应。有必要进一步调查该领域的靶向治疗机会。

HPV-associated oropharynx carcinoma (HPVOPC) tumors have a relatively low mutational burden. Elucidating the relative contributions of other tumor alterations, such as DNA methylation alterations, alternative splicing events (ASE), and copy number variation (CNV), could provide a deeper understanding of carcinogenesis drivers in this disease. We applied network propagation analysis to multiple classes of tumor alterations in a discovery cohort of 46 primary HPVOPC tumors and 25 cancer-unaffected controls and validated our findings with TCGA data. We identified significant overlap between differential gene expression networks and all alteration classes, and this association was highest for methylation and lowest for CNV. Significant overlap was seen for gene clusters of G protein-coupled receptor (GPCR) pathways. HPV16-human protein interaction analysis identified an enriched cluster defined by an immune-mediated GPCR signal, including CXCR3 cytokines CXCL9, CXCL10, and CXCL11. CXCR3 was found to be expressed in primary HPVOPC, and scRNA-seq analysis demonstrated CXCR3 ligands to be highly expressed in M2 macrophages. In vivo models demonstrated decreased tumor growth with antagonism of the CXCR3 receptor in immunodeficient but not immunocompetent mice, suggesting that the CXCR3 axis can drive tumor proliferation in an autocrine fashion, but the effect is tempered by an intact immune system. In conclusion, methylation, ASE, and SNV alterations are highly associated with network gene expression changes in HPVOPC, suggesting that ASE and methylation alterations have an important role in driving the oncogenic phenotype. Network analysis identifies GPCR networks, specifically the CXCR3 chemokine axis, as modulators of tumor-immune interactions that may have proliferative effects on primary tumors as well as a role for immunosurveillance; however, CXCR3 inhibition should be used with caution, as these agents may both inhibit and stimulate tumor growth considering the competing effects of this cytokine axis. Further investigation is needed to explore opportunities for targeted therapy in this setting.