The development, progression, and curative efficacy of head and neck squamous cell carcinoma (HNSCC) are influenced by complex interactions between epithelial and immune cells. Nevertheless, the specific changes in the nature of these interactions and their underlying molecular mechanisms in HNSCC are not yet fully understood. Cuproptosis, a form of programmed cell death that is dependent on copper, has been implicated in cancer pathogenesis. However, the understanding of cuproptosis in the context of HNSCC remains limited. In this study, we have discovered that cuproptosis-related long non-coding RNAs (CRLs) known as JPX play a role in promoting the expression of the oncogene urokinase-type plasminogen activator (PLAU) by competitively binding to miR-193b-3p in HNSCC. The increased activity of the JPX/miR-193b-3p/PLAU axis in malignant epithelial cells leads to enhanced cell proliferation, migration, and invasion in HNSCC. Moreover, the overexpression of PLAU in tumor epithelial cells facilitates its interaction with the receptor PLAUR, predominantly expressed on macrophages, thereby influencing the abnormal epithelial–immune interactome in HNSCC. Notably, the JPX inhibitor Axitinib and the PLAU inhibitor Palbociclib may not only exert their effects on the JPX/miR-193b-3p/PLAU axis that impacts the malignant tumor behaviors and the epithelial–immune cell interactions but also exhibit synergistic effects in terms of suppressing tumor cell growth and arresting cell cycle by targeting epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK4/6) for the treatment of HNSCC.

头颈部鳞状细胞癌 （HNSCC） 的发生、进展和疗效受上皮细胞和免疫细胞之间复杂相互作用的影响。然而，这些相互作用性质的具体变化及其在 HNSCC 中的潜在分子机制尚不完全清楚。铜癌是一种依赖于铜的程序性细胞死亡形式，与癌症发病机制有关。然而，在 HNSCC 背景下对 cuproptosis 的理解仍然有限。在这项研究中，我们发现称为 JPX 的铜蛋白病相关长链非编码 RNA （CRL） 通过与 HNSCC 中的 miR-193b-3p 竞争性结合，在促进癌基因尿激酶型纤溶酶原激活剂 （PLAU） 的表达中发挥作用。恶性上皮细胞中 JPX/miR-193b-3p/PLAU 轴活性的增加导致 HNSCC 细胞增殖、迁移和侵袭增强。此外，PLAU 在肿瘤上皮细胞中的过表达促进了其与主要在巨噬细胞上表达的受体 PLAUR 的相互作用，从而影响 HNSCC 中异常的上皮-免疫相互作用组。值得注意的是，JPX 抑制剂阿昔替尼和 PLAU 抑制剂 Palbociclib 不仅可能对 JPX/miR-193b-3p/PLAU 轴产生影响恶性肿瘤行为和上皮-免疫细胞相互作用的作用，而且还通过靶向表皮生长因子受体 （EGFR） 和细胞周期蛋白依赖性激酶 （CDK4/6） 治疗 HNSCC 在抑制肿瘤细胞生长和阻止细胞周期方面表现出协同作用。