Spatial architecture of immunometabolism: Mitochondrial‑organelle interfaces in immune signaling (Review).

Metabolic reprogramming is fundamental to immune cell function, yet the spatial architecture that organizes these metabolic states remains incompletely defined. Rather than functioning as isolated bioenergetic units, mitochondria act as spatial hubs embedded within dynamic organelle networks that coordinate immuno‑metabolic signaling. In the present review, the structural and functional basis of mitochondrial organelle interfaces were delineated, including membrane contact sites and vesicular trafficking pathways, with the endoplasmic reticulum, lysosomes, peroxisomes, lipid droplets and the nucleus. It was discussed how these interfaces generate specialized microdomains for the localized exchange of calcium, lipids and redox signals, thereby shaping innate and adaptive effector programs. It was further highlighted how mitochondria‑derived vesicles and mitochondria‑containing extracellular vesicles extend this regulatory axis, linking intracellular organelle crosstalk directly to systemic tissue homeostasis. Crucially, maladaptive decoupling of these interface circuits emerges as a recurrent feature of infection, sepsis, cancer, autoimmunity and chronic inflammation diseases. Finally, emerging interface‑targeted therapeutic strategies were evaluated and the technical methodologies required to validate nanoscale interactions were critically assessed. By conceptualizing immunometabolism as a spatially coordinated process, the prsent review provides a comprehensive landscape for decoding immune signaling and identifies tractable avenues for precision immunotherapy.