Decline of immunity is an epidemiological feature of opioid addicts.Recent work reveals a landscape of peripheral immune microenvironment in opioid addicts.Opioid addicts exhibit a significant expansion of fragile-like regulatory T cells(Tregs)and enhanced Treg-derived interferon-y(IFN-γ)expression.IFN-γ signaling reshapes synaptic morphology in nucleus accumbens(NAc)neurons,modulating subsequent withdrawal symptoms.Treg fragility transformation from WT Tregs is primarily due to opioid-induced global hypoxia during acute withdrawal period.Opioids increase the expression of neuron-derived C-C motif chemokine ligand 2(Ccl2)and disrupt blood-brain barrier(BBB)integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7(Fabp7),both of which trigger peripheral Treg infiltration into NAc.Recent studies suggest that subtle homeostatic changes in the peripheralimmune milieu may also contribute to modulating synapses that are responsible for addictive behaviors,which may lead to the development of new therapeutic strategies.