These findings strongly suggest that PRRs-independent mechanisms—such as STING gain-of-function mutations, ER stress, trafficking defects (e.g., COPA syndrome), impaired lysosomal degradation (e.g., Niemann–Pick type C), and cell death–associated stress responses—are critical but underappreciated drivers of STING signaling. The gene discussed is STING1; the disease is autoimmune interstitial lung disease-arthritis syndrome.