Abstract

Myeloid cells, including monocytes, macrophages, dendritic cells, and granulocytes, constitute a versatile arm of the immune system, serving as frontline sentinels that detect and react to environmental cues and orchestrate tailored immune responses. Their ability to respond promptly to distinct threats depends on dynamic processes that include differentiation, antigen presentation, and secretion of pro-inflammatory and antimicrobial mediators. These functions are tightly linked to the integrity of the endoplasmic reticulum (ER), an essential organelle responsible for synthesis, folding, and modification of proteins. Disruption of ER homeostasis is commonly induced by infection, inflammation, autoimmunity, or cancer settings, leading to ER stress and activation of the unfolded protein response (UPR), a 3-pronged signaling pathway aiming to restore the fidelity of the cellular proteome. Among UPR branches, the inositol-requiring enzyme 1 (IRE1)/XBP1 pathway has emerged as a central regulator of myeloid cell function, integrating proteostatic stress with immune modulation. Despite growing evidence positioning the IRE1/XBP1s axis as a pivotal immunological target bearing biomedical potential, the context-dependent outcomes of this UPR branch in myeloid cells, ranging from protective to maladaptive, remain incompletely understood. In this review, we explore the multifaceted roles of IRE1 in shaping myeloid cell responses across physiological and pathological states, highlighting molecular mechanisms and their impact on immune homeostasis and disease pathogenesis. This review provides a comprehensive overview of how the endoplasmic reticulum stress sensor inositol-requiring enzyme 1 orchestrates myeloid cell fate and function, balancing immunity and pathology through context-specific signaling across infection, inflammation, autoimmunity, and cancer.