Recent preclinical and clinical studies have confirmed the essential role of interferons in the host’s immune response against malignant cells. Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer strongly associated with Merkel cell polyomavirus (MCPyV). Despite progress in understanding MCC pathogenesis, the role of innate immune signaling, particularly interferon-γ (IFN γ) and its downstream pathways, remains underexplored. This review summarizes recent findings on IFN-γ in MCC, highlighting its dual role in promoting both antitumor immunity and immune evasion. IFN-γ enhances cytotoxic T cell responses, upregulates MHC class I/II expression, and induces tumor cell apoptosis. Transcriptomic studies have shown that IFN-γ treatment upregulates immune-regulatory genes including PD-L1, HLA-A/B/C, and IDO1 by over threefold; it also activates APOBEC3B and 3G, contributing to antiviral defense and tumor editing. Clinically, immune checkpoint inhibitors (ICIs) such as pembrolizumab and avelumab yield objective response rates of 30–56% and two-year overall survival rates exceeding 60% in advanced MCC. However, approximately 50% of patients do not respond, in part due to IFN-γ signaling deficiencies. This review further discusses IFN-γ’s crosstalk with the STAT1/3/5 pathways and emerging combination strategies aimed at restoring immune sensitivity. Understanding these mechanisms may inform personalized immunotherapeutic approaches and guide the development of IFN-γ–based interventions in MCC.
近期临床前及临床研究证实，干扰素在宿主对抗恶性细胞的免疫应答中发挥关键作用。默克尔细胞癌（MCC）是一种罕见且侵袭性强的皮肤癌，与默克尔细胞多瘤病毒（MCPyV）密切相关。尽管对MCC发病机制的认识有所进展，但先天免疫信号通路（特别是干扰素-γ及其下游通路）的作用仍未得到充分探索。本综述总结了关于IFN-γ在MCC中的最新发现，重点阐述其在促进抗肿瘤免疫和介导免疫逃逸中的双重作用。IFN-γ能增强细胞毒性T细胞反应，上调MHC I/II类分子表达，并诱导肿瘤细胞凋亡。转录组学研究表明，IFN-γ处理可使PD-L1、HLA-A/B/C和IDO1等免疫调节基因表达上调超过三倍；同时激活APOBEC3B和3G，参与抗病毒防御和肿瘤编辑过程。临床上，帕博利珠单抗和阿维鲁单抗等免疫检查点抑制剂在晚期MCC中可实现30-56%的客观缓解率，两年总生存率超过60%。但约50%患者无应答，部分原因在于IFN-γ信号通路缺陷。本文进一步探讨了IFN-γ与STAT1/3/5通路的交互作用，以及旨在恢复免疫敏感性的新兴联合治疗策略。深入理解这些机制可为个体化免疫治疗方案的制定提供依据，并指导基于IFN-γ的MCC干预策略开发。
IFN γ and the IFN γ Signaling Pathways in Merkel Cell Carcinoma
肿瘤(癌症)患者之家