Targeting TMED4 enhances CD8 <sup>+</sup> T cell function and CAR T cell efficacy in solid tumors through the IRE1α-autophagy axis
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 1α (IRE1α)–X-box binding protein 1 (XBP1) axis and induced autophagy flux in an IRE1α-dependent manner. Genetic deletion of Ern1 (IRE1α) 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 IRE1α-driven autophagy, establishing TMED4 as a promising immunotherapeutic target for improving CAR T cell efficacy.
Authors
- Zhenyan Jiang (ORCID: https://orcid.org/0000-0003-4594-7065)
- E Wu (ORCID: https://orcid.org/0000-0003-4587-6420)
- Alexandra Aicher (ORCID: https://orcid.org/0000-0002-8920-9577)
- Yuexiao Tao (ORCID: https://orcid.org/0000-0003-3820-0553)
- Youqiong Ye (ORCID: https://orcid.org/0000-0001-8332-4710)
- Ming Qin (ORCID: https://orcid.org/0000-0001-5633-3988)
- Licai Shi
- Huizi Wang (ORCID: https://orcid.org/0000-0002-3652-6210)
- Christopher Heeschen (ORCID: https://orcid.org/0000-0002-1158-8554)
- Ke Jiang (ORCID: https://orcid.org/0000-0001-7959-7716)
- Chu-Hu Lai (ORCID: https://orcid.org/0000-0003-0643-2376)
- Xuefeng Wu (ORCID: https://orcid.org/0000-0002-6933-7280)
- Yu Cao
- Xin Li (ORCID: https://orcid.org/0000-0003-2999-9818)
- Li J (ORCID: https://orcid.org/0000-0002-6679-5227)
- Lin Xu (ORCID: https://orcid.org/0000-0002-6889-0279)
- Guang Chen (ORCID: https://orcid.org/0000-0003-0336-0100)
- Jiamin Liu (ORCID: https://orcid.org/0009-0007-9802-5562)
- Jun Ni (ORCID: https://orcid.org/0009-0002-6105-9455)
- Shuyao Wu
- Sophia Jiaxin Wu (ORCID: https://orcid.org/0009-0006-3946-8307)
Institutions
- Zunyi Medical University (CN)
- Shanghai Jiao Tong University (CN)
- China Medical University (TW)
- Peking University (CN)
- Ruijin Hospital (CN)
- Shenzhen Bay Laboratory (CN)
- Tongren Hospital (CN)
- Shanghai Cancer Institute (CN)
- Candiolo Cancer Institute (IT)
Publication Details
- Journal
- Science Advances
- Published
- 2026-06-12
- DOI
- https://doi.org/10.1126/sciadv.aee0517
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Innovative Research Team of High-level Local University in Shanghai
- National Natural Science Foundation of China
- Ministero della Salute
- Shanghai Municipal Education Commission
- Ministry of Science and Technology, Taiwan
- Associazione Italiana per la Ricerca sul Cancro
- Ministry of Education, Kenya
- National Key Research and Development Program of China
- Science and Technology Innovation Plan Of Shanghai Science and Technology Commission