Int Immunopharmacol. 2026 Mar 16;177:116509. doi: 10.1016/j.intimp.2026.116509. Online ahead of print.
ABSTRACT
The DNA damage response (DDR) is considered a pivotal regulator of immune activation, in which genomic stress serves as an interface between genomic biochemistry and innate and adaptive immunity. Recent discoveries have shown that the mitotic kinase BUB1 has non-canonical cytoplasmic roles, including regulating the accumulation and recognition of endogenous double-stranded RNA (dsRNA) generated under stress conditions of genotoxicity. BUB1 increases type I interferon signalling via RIG-I/MDA5 and controls cytokine production, interferon-stimulated gene transcription, and antitumor immune surveillance, particularly after radiotherapy, but also promotes persistent inflammation by perpetuating signalling. In addition, insulin-like growth factor-like family 2 (IGFL2), secreted by activated and exhausted T-cells, has been identified as a potent mediator of the T-cell-monocyte-fibroblast crosstalk that drives inflammatory myeloid programming, fibroblast activation, and tissue regeneration. This sensing of BUB1-regulated expression of the extracellular (dsRNA) and the stromal remodelling mediated by IGFL2 can be considered a pathogenic interface between DDR activation and the inflammatory response of the maladaptive immune response. These revelations ensure that BUB1 and IGFL2 are core immunoregulatory nodes upon which therapeutic actions are understood in accurate oncology, immunotherapy, and the control of autoimmune diseases.
PMID:41846061 | DOI:10.1016/j.intimp.2026.116509