Innate immune responses are considered to play crucial roles in the progression of Alzheimer's disease (AD). Recently, immunotherapy is emerging as an innovative and highly conceivable strategy for AD treatment. The cGAMP-STING-IRF3 signaling pathway plays a pivotal role in mediating innate immune responses. In this study, we provide pioneering investigation to find that the STING stimulator, cGAMP, significantly ameliorates cognitive deficits, improves pathological changes, decreases Aβ plaque load and reduces neuron apoptosis in APP/PS1 transgenetic mice. The stimulation of cGAMP-STING-IRF3 pathway induces expression of triggering receptor expressed on myeloid cells 2 (TREM2), and the overexpression of TREM2 further decreases Aβ deposition and neuron loss while improves AD pathomorphology and cognitive impairment. Additionally, TREM2 regulates microglia polarization from M1 towards M2 phenotype thereby achieves reduction of neuroinflammation in AD. These findings support that the enhancement of TREM2 exerts beneficial effects in ameliorating AD development. Taken together, our results demonstrate that cGAMP is a potential candidate for applications in Alzheimer's disease immunotherapy.