The role of mTORC2/RICTOR in immune cells and inflammatory diseases

Abstract

mTORC2, defined by its core component RICTOR, is a key regulator of immune cell function and inflammation, yet its roles have long been underappreciated due to lack of specific inhibitors and in vivo tools. This review summarizes the current understanding of mTORC2-specific signaling (via AKT, SGK1, and PKC) in regulating the development, differentiation, and effector functions of diverse immune cells, and discusses its emerging roles in immune cell inflammation and tissue-specific inflammation. We synthesized findings from recent studies using conditional knockout mouse models, pharmacological inhibitors, and clinical samples. mTORC2 controls Th1/Th2 differentiation, Treg stability, and memory T cell formation; regulates BCR signaling and plasma cell survival; and modulates macrophage M2 polarization, DC maturation, and NK cell function. In tissue inflammation, mTORC2 plays context-dependent roles—exacerbating osteoarthritis and pancreatitis but restraining pro-inflammatory polarization in colorectal cancer. Dual mTORC1/2 inhibitors (e.g., AZD2014) have shown early promise, though challenges remain regarding efficacy, toxicity, and immunomodulatory complexity.