This review provides an overview of the latest research exploring the role of immune and metabolic pathways in depression. Findings from large-scale cohorts and biobanks, including studies using -omics technologies, consistently point toward an involvement of immuno-metabolic dysregulations in depression. Alterations in these biological pathways may explain the considerable comorbidity between depression and cardiometabolic conditions and represent a promising target for intervention. Specific depression clinical profiles are described, such as atypical neurovegetative symptoms, that are more strongly connected with immuno- metabolic alterations. These alterations are linked to brain circuits involved in energy homeostasis, potentially connecting peripheral immuno-metabolic dysregulations with specific behavioral symptom profiles. Further, a new generation of ongoing clinical trials is discussed that test treatment add-ons targeting immunometabolic pathways in subsets of depressed patients, selected based on specific bioclinical profiles. Findings highlight the potential for a stratified approach to depression treatment based on underlying immuno-metabolic dysregulations.