IFNγ, a pleiotropic cytokine produced not only by activated lymphocytes but also in response to cancer immunotherapies, has both antitumor and tumor-promoting functions. In ovarian cancer (OC) cells, the tumor-promoting functions of IFNγ are mediated by IFNγ-induced expression of Bcl3, PD-L1 and IL-8/CXCL8, which have long been known to have critical cellular functions as a proto-oncogene, an immune checkpoint ligand and a chemoattractant, respectively. However, overwhelming evidence has demonstrated that these three genes have tumor-promoting roles far beyond their originally identified functions. These tumor-promoting mechanisms include increased cancer cell proliferation, invasion, angiogenesis, metastasis, resistance to chemotherapy and immune escape. Recent studies have shown that IFNγ-induced Bcl3, PD-L1 and IL-8 expression is regulated by the same JAK1/STAT1 signaling pathway: IFNγ induces the expression of Bcl3, which then promotes the expression of PD-L1 and IL-8 in OC cells, resulting in their increased proliferation and migration. In this review, we summarize the recent findings on how IFNγ affects the tumor microenvironment and promotes tumor progression, with a special focus on ovarian cancer and on Bcl3, PD-L1 and IL-8/CXCL8 signaling. We also discuss promising novel combinatorial strategies in clinical trials targeting Bcl3, PD-L1 and IL-8 to increase the effectiveness of cancer immunotherapies.
干扰素γ（IFNγ）作为一种多效性细胞因子，不仅由活化淋巴细胞产生，也在癌症免疫治疗应答中表达，兼具抗肿瘤与促肿瘤双重功能。在卵巢癌细胞中，IFNγ的促肿瘤作用主要通过诱导Bcl3、PD-L1及IL-8/CXCL8的表达实现——这三种分子分别作为原癌基因、免疫检查点配体和趋化因子，其关键细胞功能早已被学界认知。然而，大量证据表明这些基因的促肿瘤作用远超其最初被发现的功能范畴，具体机制包括增强癌细胞增殖、侵袭、血管生成、转移能力，以及促进化疗耐药和免疫逃逸。最新研究揭示，IFNγ诱导的Bcl3、PD-L1和IL-8表达受同一JAK1/STAT1信号通路调控：IFNγ诱导Bcl3表达，进而促进卵巢癌细胞中PD-L1与IL-8的表达，最终增强癌细胞增殖与迁移能力。本综述系统总结了IFNγ影响肿瘤微环境及促进肿瘤进展的最新发现，特别聚焦于卵巢癌中Bcl3、PD-L1和IL-8/CXCL8信号通路的作用机制，并探讨了针对这三类靶点的联合治疗策略在临床试验中的应用前景，以提升癌症免疫疗法的疗效。
IFNγ-Induced Bcl3, PD-L1 and IL-8 Signaling in Ovarian Cancer: Mechanisms and Clinical Significance
肿瘤(癌症)患者之家