Interferon-gamma (IFN-γ) is a critical cytokine that plays a pivotal role in immune system regulation. It is a key mediator of both cellular defense mechanisms and antitumor immunity. As the sole member of the type II interferon family, IFN-γ modulates immune responses by activating macrophages, enhancing natural killer cell function, and regulating gene expression across multiple cellular processes. Alternative splicing is a post-transcriptional gene expression regulatory mechanism that generates multiple mature messenger RNAs from a single gene, dramatically increasing proteome diversity without the need of a proportional genome expansion. This process occurs in 90–95% of human genes, with alternative splicing events allowing for the production of diverse protein isoforms that can have distinct—or even opposing—functional properties. Alternative splicing plays a crucial role in cancer immunology, potentially generating tumor neoepitopes and modulating immune responses. However, how alternative splicing affects IFN-γ’s activity is still poorly understood. This review explores how alternative splicing regulates the expression and function of both upstream regulators and downstream effectors of IFN-γ, revealing complex mechanisms of gene expression and immune response modulation. Key transcription factors and signaling molecules of the IFN-γ pathway are alternatively spliced, and alternative splicing can dramatically alter IFN-γ signaling, immune cell function, and response to environmental cues. Specific splice variants can enhance or inhibit IFN-γ-mediated immune responses, potentially influencing cancer immunotherapy, autoimmune conditions, and infectious disease outcomes. The emerging understanding of these splicing events offers promising therapeutic strategies for manipulating immune responses through targeted molecular interventions.
干扰素-γ（IFN-γ）是一种关键的细胞因子，在免疫系统调节中发挥着核心作用。它是细胞防御机制和抗肿瘤免疫的关键介质。作为II型干扰素家族的唯一成员，IFN-γ通过激活巨噬细胞、增强自然杀伤细胞功能以及调控多个细胞过程中的基因表达来调节免疫反应。可变剪接是一种转录后基因表达调控机制，能够从单个基因产生多种成熟信使RNA，从而在无需基因组相应扩增的情况下显著增加蛋白质组的多样性。这一过程发生在90-95%的人类基因中，通过可变剪接事件产生具有不同甚至相反功能特性的多种蛋白质亚型。可变剪接在癌症免疫学中起着至关重要的作用，可能产生肿瘤新抗原并调节免疫反应。然而，可变剪接如何影响IFN-γ的活性仍知之甚少。本综述探讨了可变剪接如何调控IFN-γ上游调节因子和下游效应因子的表达与功能，揭示了基因表达和免疫反应调控的复杂机制。IFN-γ通路的关键转录因子和信号分子均可发生可变剪接，且可变剪接可显著改变IFN-γ信号传导、免疫细胞功能及对环境信号的应答。特定的剪接变体能够增强或抑制IFN-γ介导的免疫反应，可能影响癌症免疫治疗、自身免疫性疾病及感染性疾病的预后。对这些剪接事件的新认识为通过靶向分子干预调控免疫反应提供了有前景的治疗策略。
Alternative Splicing as a Modulator of the Interferon-Gamma Pathway
肿瘤(癌症)患者之家