Neuronal activation of the STING pathway is implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study reveals that STING is activated in vulnerable cortical and spinal motor neurons in both familial (fALS) and sporadic (sALS) ALS, but not in less affected neurons. This activation is consistent across human postmortem tissue, mouse models of C9orf72-related ALS/FTD, and human iPSC-derived neurons. STING activation occurs in a neuron-autonomous manner, driven by DNA damage, and is associated with increased downstream inflammatory markers. STING inhibition reduces these inflammatory signals in fALS iPSC-derived neurons, suggesting a key role for the STING pathway in neuronal inflammation in ALS. The study also shows that DNA damage, whether from pathological processes like TDP-43 depletion or C9orf72 dipeptide repeat proteins, activates the STING pathway, leading to innate immune responses. These findings highlight the importance of STING signaling in neuroinflammation and neuronal vulnerability in ALS and FTD. The results indicate that the STING pathway is a critical component of the innate immune response in neurons, contributing to the pathogenesis of these neurodegenerative diseases.Neuronal activation of the STING pathway is implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study reveals that STING is activated in vulnerable cortical and spinal motor neurons in both familial (fALS) and sporadic (sALS) ALS, but not in less affected neurons. This activation is consistent across human postmortem tissue, mouse models of C9orf72-related ALS/FTD, and human iPSC-derived neurons. STING activation occurs in a neuron-autonomous manner, driven by DNA damage, and is associated with increased downstream inflammatory markers. STING inhibition reduces these inflammatory signals in fALS iPSC-derived neurons, suggesting a key role for the STING pathway in neuronal inflammation in ALS. The study also shows that DNA damage, whether from pathological processes like TDP-43 depletion or C9orf72 dipeptide repeat proteins, activates the STING pathway, leading to innate immune responses. These findings highlight the importance of STING signaling in neuroinflammation and neuronal vulnerability in ALS and FTD. The results indicate that the STING pathway is a critical component of the innate immune response in neurons, contributing to the pathogenesis of these neurodegenerative diseases.