Krieg Arthur M
RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
J Immunother Cancer. 2025 Sep 18;13(9):e012165. doi: 10.1136/jitc-2025-012165.
The role of type I interferon (IFN) in mediating tumor immunosurveillance, in situ vaccination, and response to other cancer immunotherapies is well established. The biologic and species-specific differences between type I IFN family members have not been sufficiently addressed. Recombinant IFN-α2 has been approved for the treatment of chronic viral infections (hepatitis B virus, hepatitis C virus) and some forms of cancer. IFN-β was approved to treat patients with multiple sclerosis but failed in the treatment of chronic viral infections or cancer. These distinct therapeutic applications most likely reflect distinct biologic roles of the individual IFNs that unfortunately remain poorly understood. IFN-β can be secreted by essentially all nucleated cells activated through most pattern recognition receptors (PRR). By contrast, IFN-α is predominantly secreted by the P1 subset of plasmacytoid dendritic cells (pDCs), which mediate viral defense and successful cancer immunotherapy following their activation by toll-like receptor (TLR)7 or TLR9 agonists. The biologic effects of TLR7 and TLR9 agonists depend critically on their structure and their ability to be processed by endosomal nucleases into fragments capable of binding two distinct agonist binding sites. The clinical activity of TLR7 and TLR9 agonists in cancer immunotherapy is associated with their induction of IFN-α secretion and P1 pDC differentiation.CD8+ T cells likely evolved for the primary purpose of killing viral/retroviral-infected cells. Immune cells detect viral/retroviral infected cells using TLR7 and TLR8 to distinguish viral GU-nucleotide-rich RNA from self-RNA modified with pseudouridine, and TLR9 to distinguish viral unmethylated CpG DNA from self-DNA modified with 5-methylcytosine. Recent studies have defined antagonist pockets in TLR7, TLR8 and TLR9 that bind degradation products of endogenous modified RNA and DNA to inhibit responses to host nucleic acids. These findings point to a role for TLR7/8/9 acting cooperatively to enable innate immunity to distinguish retroviral particles from apoptotic blebs, with important implications for optimising in situ vaccination and other cancer immunotherapy strategies, and treating systemic autoimmune diseases mediated by the inappropriate activation of TLR7/8/9 by apoptotic debris.
I型干扰素（IFN）在介导肿瘤免疫监视、原位疫苗接种以及对其他癌症免疫疗法的反应中的作用已得到充分确立。I型干扰素家族成员之间的生物学和物种特异性差异尚未得到充分研究。重组IFN-α2已被批准用于治疗慢性病毒感染（乙型肝炎病毒、丙型肝炎病毒）和某些形式的癌症。IFN-β被批准用于治疗多发性硬化症患者，但在治疗慢性病毒感染或癌症方面失败。这些不同的治疗应用很可能反映了各个IFN的独特生物学作用，遗憾的是，目前对这些作用仍知之甚少。IFN-β基本上可以由通过大多数模式识别受体（PRR）激活的所有有核细胞分泌。相比之下，IFN-α主要由浆细胞样树突状细胞（pDC）的P1亚群分泌，这些细胞在被Toll样受体（TLR）7或TLR9激动剂激活后介导病毒防御和成功的癌症免疫治疗。TLR7和TLR9激动剂的生物学效应关键取决于它们的结构以及被内体核酸酶加工成能够结合两个不同激动剂结合位点的片段的能力。TLR7和TLR9激动剂在癌症免疫治疗中的临床活性与其诱导IFN-α分泌和P1 pDC分化有关。CD8+ T细胞可能最初进化的主要目的是杀死病毒/逆转录病毒感染的细胞。免疫细胞使用TLR7和TLR8来区分富含病毒GU核苷酸的RNA与用假尿苷修饰的自身RNA，并使用TLR9来区分病毒未甲基化的CpG DNA与用5-甲基胞嘧啶修饰的自身DNA，从而检测病毒/逆转录病毒感染的细胞。最近的研究已经确定了TLR7、TLR8和TLR9中的拮抗剂口袋，这些口袋结合内源性修饰的RNA和DNA的降解产物以抑制对宿主核酸的反应。这些发现表明TLR7/8/9协同作用，使先天免疫能够区分逆转录病毒颗粒和凋亡小泡，这对于优化原位疫苗接种和其他癌症免疫治疗策略以及治疗由凋亡碎片不适当激活TLR7/8/9介导的全身性自身免疫疾病具有重要意义。
