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

Area of Science:

• Immunology
• Cancer Biology
• Cellular Stress Response

Background:

• Endoplasmic reticulum stress (ERS) and autophagy are crucial for T cell function in tumors.
• Mechanisms linking ERS, autophagy, and T cell exhaustion are not fully understood.

Purpose of the Study:

• To investigate the role of TMED4 in CD8+ T cell antitumor immunity.
• To elucidate the molecular mechanisms by which TMED4 influences T cell function and exhaustion.

Main Methods:

• T cell-specific Tmed4 deletion mouse models.
• Analysis of CD8+ T cell proliferation, infiltration, and killing capacity.
• Investigation of the IRE1α-XBP1 signaling pathway and autophagy flux.
• Chimeric antigen receptor T cell (CAR T cell) assays.
• Pharmacological inhibition of TMED4 using antisense oligonucleotides.

Main Results:

• Tmed4 deletion in T cells enhanced antitumor immunity by increasing CD8+ T cell proliferation, infiltration, and cytotoxic activity.
• Tmed4 deficiency led to reduced terminal T cell exhaustion.
• TMED4 deficiency activated the IRE1α-XBP1 axis and induced autophagy flux in an IRE1α-dependent manner.
• Genetic deletion of IRE1α (Ern1) or Beclin1 (Becn1) abrogated the antitumor benefits of Tmed4 deficiency.
• TMED4-deficient CAR T cells showed improved antitumor efficacy.
• Antisense oligonucleotide-mediated inhibition of TMED4 enhanced tumor control.

Conclusions:

• TMED4 is a critical negative regulator of CD8+ T cell effector function and promotes terminal exhaustion.
• TMED4 controls T cell function via IRE1α-dependent autophagy.
• Targeting TMED4 represents a promising strategy for enhancing T cell-based immunotherapies, including CAR T cells.