Barrier Immun. 2026 May 4. doi: 10.1002/dni2.70011. Online ahead of print.
ABSTRACT
Immunity has traditionally been viewed through the lens of extracellular pathogen recognition and intercellular immune communication. However, emerging evidence reveals that immune regulation extends deeply into the intracellular space, where organelles function and metabolism as active immune signaling platforms. In this review, we synthesize recent advances that redefine immunity as a multiscale system integrating extracellular, intercellular, and intracellular immune mechanisms. We first outline the functional modules of intracellular immune sensing and inflammatory signaling, including plasma membrane recognition, cytosolic surveillance, inflammasome activation, membrane execution, and secretome-mediated outputs. We then present a systematic framework of organelle-based platforms that regulate intracellular immunity and inflammation. Among these, mitochondria emerge as central immune organelles that coordinate metabolic reprogramming, danger/damage signal sensing, and inflammatory activation. Beyond their canonical role in bioenergetics, mitochondria engage in dynamic organelle crosstalk, transmit immune signals through soluble mediators, metabolites and contact sites, and participate in intercellular mitochondrial transfer. We classify mitochondrial immune signaling into three principal modes: indirect signaling via soluble mediators, direct organelle crosstalk at mitochondrial contact sites, and intercellular mitochondrial transfer, highlighting how these mechanisms integrate metabolism with immune regulation. Finally, we summarize current clinical and translational immunotherapies across multiple immune layers, spanning barrier immunity, innate immunity, adaptive immunity, and intracellular immunity. Collectively, this review provides a new conceptual and mechanistic framework for intracellular immune regulation and underscores emerging therapeutic opportunities arising from targeting organelle-based immune pathways.
PMID:42158841 | PMC:PMC13183392 | DOI:10.1002/dni2.70011