Tnfrsf4, also known as OX40 (CD134), is a member of the tumour necrosis factor receptor family and functions as a T cell co-stimulatory molecule [1]. It is activated by its cognate ligand OX40L (CD134L, CD252). The interactions of Tnfrsf4 and OX40L promote T cell survival, effector T cell phenotype, T cell memory, and increase effector cytokine production. This pathway is involved in multiple immunological pathways such as Th2, Th1, Th17 and Th22, and is critical for the expansion, differentiation, and survival of effector and memory T cells [1,7,9].

In various diseases, Tnfrsf4 has shown distinct impacts. In autoimmunity, the OX40-OX40L interaction has been proposed as a potential therapeutic target [1]. In nasopharyngeal carcinoma, TNFRSF4+ Treg cells might contribute to immune-suppression in the tumour microenvironment [2]. In thyroid-associated ophthalmopathy, increased activity of the TNFSF4/TNFRSF4 interaction was observed [3]. In chronic myeloid leukemia, Tnfrsf4-expressing Tregs promote immune escape of leukemia stem cells, and TNFRSF4 could be a potential target to boost antileukemic immunity [4]. In hepatocellular carcinoma, TNFRSF4 expression affects immune cell infiltration, gene mutation, and patient prognosis [5]. In esophageal squamous cell carcinoma, TNFRSF4+CD4+ Tregs with activated immunosuppressive function are enriched in post-treatment tumors from non-responders [6]. In non-M3 acute myeloid leukemia, elevated TNFRSF4 gene expression is a predictor of poor prognosis [8]. In atopic dermatitis, the expression of Tnfrsf4 and its ligand is increased, and targeting the OX40 pathway shows promise as a therapeutic approach [9].

In conclusion, Tnfrsf4 is a crucial T cell co-stimulatory molecule involved in multiple immunological processes. Its role in various diseases, such as autoimmunity, cancers, and inflammatory diseases, has been revealed through different research models. The study of Tnfrsf4 provides insights into disease mechanisms and potential therapeutic targets for these conditions.