REGULATORY T CELL DYSFUNCTION IN CHRONIC INFLAMMATORY DISEASES: ROLE OF PI3K/AKT-DRIVEN FOXP3 INSTABILITY WITH IMPLICATIONS FOR INFECTIOUS DISEASES, CANCER, AND ONE HEALTH

The PI3K/AKT/mTOR signalling pathway is a central molecular checkpoint that governs the stability, metabolic fitness, and suppressive function of FOXP3+ regulatory T cells. This review provides a comprehensive synthesis of how dysregulated signalling within this axis contributes to the pathogenesis of autoimmunity, cancer, and chronic infectious diseases. In autoimmune situations, such as psoriasis, hyperactivation of the AKT1 isoform promotes the K48-linked ubiquitination and subsequent degradation of FOXP3, leading to a loss of immune tolerance. Conversely, in oncology, sustained PI3K/AKT signalling in the tumour microenvironment supports Treg-mediated immune evasion; targeting this axis with small-molecule inhibitors can selectively deplete tumour-resident Tregs, thereby enhancing anti-tumour immunity. The pathway also plays a complex role in chronic infections. While pathogens like M. tuberculosis have been shown to inhibit PI3K/AKT/mTOR signalling to facilitate Treg expansion and evade host defence, HIV infection presents a distinct mechanism. In HIV+ individuals, activation of AKT1 and PD-1 has been linked to the stability and expansion of dysfunctional FOXP3+ cells, which contribute to persistent immune activation and disease progression. By integrating these diverse clinical findings, we highlight the PI3K/AKT/mTOR axis as a high-priority therapeutic target for "reprogramming" Treg identity to restore immune homeostasis across a spectrum of chronic inflammatory conditions.