The OX40-OX40L Co-Stimulatory Pathway as a Shared Driver of Immune Persistence in Skin and Airway Inflammation.

The OX40-OX40L co-stimulatory pathway has emerged as an important regulator of T-cell persistence and immune memory. While traditionally associated with type 2 inflammation, its role extends across multiple barrier tissues, including the skin and respiratory mucosa, where it integrates epithelial signals with adaptive immune responses. To provide a comprehensive and integrative overview of the OX40-OX40L axis as a shared driver of immune persistence across skin and airway inflammatory diseases and to discuss its therapeutic implications. A narrative review was conducted based on a focused literature search of PubMed, Scopus, and Web of Science up to February 2026. Experimental, translational, and clinical studies addressing OX40-OX40L biology and therapeutic targeting were included. OX40 signaling acts as a late co-stimulatory pathway that sustains effector T-cell survival, promotes tissue-resident memory T-cell formation, and modulates regulatory T-cell function. In barrier tissues, epithelial-derived alarmins such as TSLP and IL-33 induce OX40L expression on antigen-presenting cells, reinforcing type 2-polarized immune responses. This axis contributes to chronic inflammation in atopic dermatitis, asthma, allergic rhinitis, and nasal polyposis, supporting the concept of shared mechanisms of immune persistence across type 2 inflammatory diseases. Beyond type 2 immunity, OX40-OX40L signaling also participates in Th1-, Th17-, and Th22-mediated responses, as well as in autoimmune, fibrosing, and lymphoproliferative disorders. Therapeutic targeting of this pathway, particularly with monoclonal antibodies such as amlitelimab, has demonstrated clinically meaningful efficacy and suggests potential for durable disease modification. The OX40-OX40L axis represents an important immunological pathway linking epithelial activation to adaptive immune memory across barrier tissues. Its role in sustaining immune persistence provides a conceptual framework for understanding chronic inflammatory diseases and supports continued investigation of therapies targeting upstream co-stimulatory pathways.