Tmed4, also known as endoplasmic reticulum stress-response protein 25 (ERS25), is a member of the transmembrane p24 trafficking protein family. It is involved in protein vesicular trafficking between the endoplasmic reticulum (ER) and Golgi compartments, and is associated with endoplasmic reticulum stress (ERS) and the nuclear factor erythroid 2-related factor 2-related (NRF2-related) antioxidant response pathways [1,3]. It has significance in maintaining cellular homeostasis and is potentially important in various biological processes and diseases [1,2]. Genetic models, such as gene knockout mouse models, are valuable for studying its functions.

In Treg-specific KO (Tmed4ΔTreg) mice, loss of Tmed4 led to defects in ERS and the NRF2-related antioxidant response, resulting in excessive reactive oxygen species (ROS). This reduced the Foxp3 stability and suppressive function of regulatory T cells (Tregs) in an IRE1α/XBP1 axis-dependent manner, causing T cell hyperactivation, an exacerbated inflammatory phenotype, and boosted antitumor immunity [1].

In conclusion, Tmed4 is crucial for maintaining the stability of Tregs and their suppressive function through the IRE1α-dependent ROS and the NRF2-related antioxidant response. The Tmed4ΔTreg mouse model has provided insights into the role of Tmed4 in tumor and autoimmune disease conditions, highlighting its potential as a therapeutic target in these areas [1].