皮肤黑色素瘤（SKCM）对皮肤癌构成了重大挑战。最近的免疫疗法突破彻底改变了黑色素瘤的治疗，但肿瘤异质性仍然是一个障碍。 DNA 甲基化精心策划的表观遗传修饰有助于肿瘤发生，从而有可能揭示黑色素瘤的预后。在这里，我们鉴定了一种干扰素-γ (IFN-g) 敏感亚型，该亚型具有良好的结果、强大的浸润性 CD8 T 细胞以及批量 RNA-seq 分析中的 IFN-g 评分。随后，我们建立了基于机器学习的 IFN-g 敏感性特征。我们在这个 10 探针特征中验证了 PSMB9 与甲基化和表达队列中的免疫治疗反应密切相关。我们假设 PSMB9 充当假定的黑色素瘤抑制因子，因为它激活 CD8 T 细胞；调节 IFN-γ 分泌的能力；以及改变大块组织中 IFN-g 受体的动力学。我们对免疫治疗患者的组织进行了单细胞 RNA 测序，以揭示 PSMB9 在激活 CD8T 细胞、增强 IFN-g 以及影响恶性细胞受体和转录因子方面的微妙作用。在两个 SKCM 细胞系中过表达 PSMB9 以模拟低甲基化状态，以证实我们的猜想。两种细胞均检测到强烈的细胞增殖和迁移抑制，表明PSMB9存在于肿瘤细胞中，并且高表达不利于肿瘤生长和迁移。总体而言，全面的综合分析表明 PSMB9 成为一种重要的预后标志物，对黑色素瘤免疫治疗具有预测潜力。这一证据不仅揭示了 PSMB9 对恶性细胞和免疫细胞的多方面影响，而且还可以作为未来免疫治疗策略的前瞻性目标。版权所有 © 2023。由 Elsevier B.V. 出版。

Skin cutaneous melanoma (SKCM) poses a significant challenge in skin cancers. Recent immunotherapy breakthroughs have revolutionized melanoma treamtment, yet tumor heterogeneity persists as an obstacle. Epigenetic modifications orchestrated by DNA methylation contributed to tumorigenesis, thus potentially unveiling melanoma prognosis. Here, we identified an interferon-gamma (IFN-g) sensitive subtype, which possesses favorable outcomes, robust infiltration CD8+T cells, and IFN-g score in bulk RNA-seq profile. Subsequently, we established an IFN-g sensitivity signature based on machine learning. We validated that PSMB9 is strongly correlated with immunotherapy response in both methylation and expression cohorts in this 10-probe signature. We assumed that PSMB9 acts as a putative melanoma suppressor, for its activation of CD8+T cell; capacity to modulate IFN-γ secretion; and dynamics altering IFN-g receptors in bulk tissue. We performed single-cell RNA-seq on immunotherapy patients' tissue to uncover the nuanced role of PSMB9 in activating CD8T + cell, enhancing IFN-g, and influencing malignant cells receptors and transcriptional factors. Overexpress PSMB9 in two SKCM cell lines to mimic the hypomethylated state to approve our conjecture. Strong cell proliferation and migration inhibition were detected on both cells, indicating that PSMB9 is present in tumor cells and that high expression is detrimental to tumor growth and migration. Overall, comprehensive integrated analysis shows that PSMB9 emerges as a vital prognostic marker, acting predictive potential regarding immunotherapy in melanoma. This evidence not only reveals the multifaceted impact of PSMB9 on both malignant and immune cells, but also serves as a prospective target for undergoing immunotherapeutic strategies in the future.Copyright © 2023. Published by Elsevier B.V.