Mitochondria orchestrated immune microenvironment and response in health and disease-clinically relevant outlook and recommendations

• Mitochondria, eukaryotic energy centers, are critical for immune regulation, supporting immune energy, signaling, and cell fate. • Immune cells show high coordination of mitochondrial metabolism, dynamics, and function. • IMT, a novel subcellular mechanism, reshapes cell metabolism/immune programs in diseases like CVD, autoimmunity, infections, aging, and tumors. • This article reviews immune cell mitochondrial changes, IMT pathways/factors, and mitochondria-mediated immune remodeling in major diseases. • Mitochondria-targeted therapies and their translation are highlighted for mechanistic research and clinical use. The homeostatic balance of the immune microenvironment is key to maintaining bodily health, and its disorder is closely related to the occurrence and development of various major diseases such as cardiovascular diseases, autoimmune diseases, tumors, and aging. In recent years, mitochondria have gradually become a research hotspot, breaking the traditional perception of mitochondria solely as the cell’s energy factory. Mitochondria precisely regulate the polarization, activation, proliferation, and functional fate of various immune cells through various means such as metabolic reprogramming, dynamics remodeling, autophagy regulation, and intercellular communication. Under pathological conditions, metabolic reprogramming abnormalities, abnormal release of mitochondrial damage-associated molecular patterns (mtDAMPs), and intercellular mitochondrial transfer (IMT) dysfunction can drive pathological remodeling of the immune microenvironment. This article provides a systematic review centered on the interaction between mitochondria and the immune microenvironment, comprehensively elaborating on aspects such as the regulatory patterns of mitochondria in immune cells, intercellular mitochondrial communication mechanisms, mitochondrial-immune remodeling pathological mechanisms in diseases, novel analytical technologies, and targeted therapeutic strategies. It analyzes the translational feasibility and challenges of mitochondria-targeted therapies, aiming to offer theoretical support and clinical reference for a deeper understanding of the immune regulatory functions of mitochondria and the development of new immunotherapeutic strategies. The review highlights that immune cell function relies on cell-type-specific mitochondrial metabolism, alongside the balance of mitochondrial dynamics and mitophagy. Furthermore, IMT and extracellular vesicle (EV)-mediated mtDAMPs signaling form a crucial intercellular communication network that regulates the energy metabolism and immune phenotype of recipient cells. Across various diseases, mitochondrial-immune remodeling points to three conserved checkpoints, providing universal therapeutic targets. Driven by breakthroughs in single-cell sequencing and multi-omics analysis, the decoding of mitochondrial heterogeneity has facilitated a paradigm shift from reactive to predictive and proactive medicine. Finally, this review integrates extensive studies on mitochondria-targeted therapeutic strategies, providing highly translatable avenues for personalized immunotherapy.