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Recombinant IFN-\u03b12 has been approved for the treatment of chronic viral infections (hepatitis B virus, hepatitis C virus) and some forms of cancer. IFN-\u03b2 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-\u03b2 can be secreted by essentially all nucleated cells activated through most pattern recognition receptors (PRR). By contrast, IFN-\u03b1 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-\u03b1 secretion and P1 pDC differentiation.<\/jats:p>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1136\/jitc-2025-012165","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T05:40:17Z","timestamp":1758260417000},"page":"e012165","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["New insights into the role of IFN-\u03b1\/\u03b2 and TLR7\/8\/9 in cancer immunotherapy and systemic autoimmunity"],"prefix":"10.1136","volume":"13","author":[{"given":"Arthur M","family":"Krieg","sequence":"first","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 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