The Role of OX40 Pathway Inhibition as a New Therapeutic Strategy for Atopic Dermatitis

Atopic dermatitis is a chronic inflammatory skin disease affecting approximately 15-20% of children and 2-10% of adults worldwide. Epidermal barrier dysfunction and immune dysregulation are central to its pathogenesis, creating a self-perpetuating cycle in which barrier disruption exacerbates inflammation, which in turn further impairs skin barrier integrity. The OX40/OX40L axis, involving the co-stimulatory receptor OX40 expressed on T cells and its ligand OX40L on antigen-presenting cells, plays a critical role in sustaining T cell-driven inflammatory responses in AD. Despite recent therapeutic advances, many patients remain inadequately controlled, and key unmet needs persist. Inhibitors of the OX40/OX40L pathway represent a novel therapeutic approach by modulating multiple effector and memory T-cell subsets implicated in disease pathogenesis. Amlitelimab, an anti-OX40L monoclonal antibody, has demonstrated sustained efficacy and a favorable safety profile in phase IIa and IIb trials. Rocatinlimab, targeting OX40, has also shown promising results in a phase IIb study and has progressed into multiple phase III trials, with supportive top-line data. In contrast, telazorlimab has shown more modest efficacy and has not advanced to later-stage development. Next-generation agents, including IMG-007, STAR-0310, APG990, and APG279, have been engineered with extended half-lives and attenuated antibody-dependent cellular cytotoxicity to support longer dosing intervals and improve tolerability. While these findings are encouraging, direct comparative studies among agents and versus established therapies are lacking, and long-term efficacy and safety data are still needed. This narrative review explores the role of the OX40/OX40L axis in atopic dermatitis pathogenesis and critically evaluates emerging therapies targeting this pathway, aiming to inform their future integration into clinical practice.