靶向 TMED4 通过 IRE1α-自噬轴增强实体瘤中 CD8⁺ T 细胞功能与 CAR-T 细胞疗效

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. Tmed4 deletion in T cells enhanced antitumor responses by promoting CD8 + T proliferation, infiltration, and killing capacity, while reducing terminal exhaustion.

Mechanistically, Tmed4 deficiency hyperactivated the inositol-requiring enzyme 1 (IRE1 )-X-box binding protein 1 (XBP1) axis and induced autophagy flux in an IRE1 -dependent manner. Genetic deletion of Ern1 (IRE1 ) or Becn1 (Beclin1) impaired the antitumor effects of Tmed4 deficiency, underscoring the role of ERS and autophagy in CD8 + T cell function.

Moreover, Tmed4 -deficient chimeric antigen receptor T cells (CAR T cells) displayed improved antitumor immunity. Pharmacological inhibition of Tmed4 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 IRE1 -driven autophagy, establishing TMED4 as a promising immunotherapeutic target for improving CAR T cell efficacy.