Biological Embedding of Adverse Childhood Experiences: Neurobiological and Immune Mechanisms Linking Early-Life Stress to Addiction Vulnerability.

Adverse childhood experiences (ACEs) are associated with elevated risk for substance use disorders (SUDs), yet prevailing accounts often emphasize psychosocial pathways and reward-circuit recalibration without fully articulating immunobiological mechanisms that may converge on these processes. This narrative review advances a biological embedding framework linking early adversity to SUD vulnerability through two partially overlapping pathways: 1) stress-reward neurodevelopmental recalibration and 2) immune embedding with downstream neuroimmune feedback. Drawing on epide- miologic and mechanistic studies across developmental psychopathology, addiction neuroscience, and psychoneuroimmunology, we synthesize evidence that ACE exposure can produce enduring alterations in stress- regulatory systems (e.g., hypothalamic-pituitary-adrenal axis and autonomic function) alongside low-grade inflammatory phenotypes characterized by altered cytokine signaling and glucocorticoid sensitivity. We then highlight convergent evidence that peripheral immune activation can influence central reward and affective processes via microglial priming, cytokine-mediated modulation of monoaminergic systems (particularly dopamine), and tryptophan-kynurenine metabolism, potentially contributing to anhedonia, negative affect, and craving-relevant reinforcement dynamics. Next, we describe limitations of the present review and of the broader evidence base, as well as priority research directions. We conclude by arguing that integrating immune embedding with stress- reward recalibration may clarify one pathway by which ACEs confer SUD vulnerability and may inform trauma- informed, neurobiologically grounded approaches to prevention and treatment.