Targeting TMED4 enhances CD8⁺ T cell function and CAR T cell efficacy in solid tumors through the IRE1α-autophagy axis.

Abstract

Endoplasmic reticulum stress (ERS) and autophagy regulate tumor-infiltrating T cell function and exhaustion, but the underlying mechanisms remain unclear. Here, we identified the ERS-related transmembrane protein TMED4 (transmembrane emp24 domain-containing 4) as a critical regulator of CD8⁺ T cell antitumor immunity. <i>Tmed4</i> deletion in T cells enhanced antitumor responses by promoting CD8⁺ T proliferation, infiltration, and killing capacity, while reducing terminal exhaustion. Mechanistically, <i>Tmed4</i> deficiency hyperactivated the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis and induced autophagy flux in an IRE1α-dependent manner. Genetic deletion of <i>Ern1</i> (IRE1α) or <i>Becn1</i> (Beclin1) impaired the antitumor effects of <i>Tmed4</i> deficiency, underscoring the role of ERS and autophagy in CD8⁺ T cell function. Moreover, <i>Tmed4</i>-deficient chimeric antigen receptor T cells (CAR T cells) displayed improved antitumor immunity. Pharmacological inhibition of <i>Tmed4</i> using antisense oligonucleotide also enhanced CD8⁺ T cell-mediated tumor control. In summary, our study reveals that TMED4 governs CD8⁺ T cell effector function and limits terminal exhaustion through IRE1α-driven autophagy, establishing TMED4 as a promising immunotherapeutic target for improving CAR T cell efficacy.