Antitumor T‐cell function requires CPEB4‐mediated adaptation to chronic endoplasmic reticulum stress.

Tumor growth is influenced by a complex network of interactions between multiple cell types in the tumor microenvironment (TME). These constrained conditions trigger the endoplasmic reticulum (ER) stress response, which extensively reprograms mRNA translation. When uncontrolled over time, chronic ER stress impairs the antitumor effector function of CD8 T lymphocytes. How cells promote adaptation to chronic stress in the TME without the detrimental effects of the terminal unfolded protein response (UPR) is unknown. Here, we find that, in effector CD8 T lymphocytes, RNA‐binding protein CPEB4 constitutes a new branch of the UPR that allows cells to adapt to sustained ER stress, yet remains decoupled from the terminal UPR. ER stress, induced during CD8 T‐cell activation and effector function, triggers CPEB4 expression. CPEB4 then mediates chronic stress adaptation to maintain cellular fitness, allowing effector molecule production and cytotoxic activity. Accordingly, this branch of the UPR is required for the antitumor effector function of T lymphocytes, and its disruption in these cells exacerbates tumor growth. Synopsis: How immune cells invading the tumor microenvironment cope with detrimental stress conditions such as hypoxia and nutrient deprivation remains poorly understood. Here, RNA‐binding protein CPEB4 is shown to mediate a novel branch of transient unfolded protein response (UTR) in CD8 T cells, supporting effector cell viability and antitumor function. Transient acute ER stress promotes CPEB4 translational upregulationCPEB4 mediates chronic ER stress adaptation in CD8 cellsT‐cell effector function requires CPEB4‐mediated chronic ER stress adaptation.CPEB4 promotes T cell‐mediated antitumor immunity in vivo. [ABSTRACT FROM AUTHOR]