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LARP4-mediated hypertranslation drives T cell dysfunction in tumors.

Yi Liu^1,2, Haochen Ni^3,4,5, Jie Li^3,4

¹Institute for Immunology, Tsinghua University, Beijing, China.

Nature Immunology

|July 22, 2025

Summary

Adoptive T-cell therapy for solid tumors faces challenges. This study reveals that the protein LARP4 drives T-cell dysfunction by altering translation, impacting anti-tumor responses.

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Area of Science:

Immunology
Molecular Biology
Cancer Research

Background:

Adoptive T-cell therapies show promise for solid tumors but are limited by T-cell dysfunction and poor persistence.
Intratumoral T-cells exhibit translatome remodeling, entering a hypertranslational state linked to acquired dysfunction.

Purpose of the Study:

To investigate the role of the RNA-binding protein LARP4 in T-cell dysfunction within the tumor microenvironment.
To determine if targeting LARP4 can enhance the efficacy of adoptive T-cell therapies.

Main Methods:

Analysis of translatome remodeling in intratumoral T-cells.
Investigating the function of LARP4 in regulating mRNA translation, specifically for oxidative phosphorylation (OXPHOS) components.
Utilizing knockout models of Larp4 in tumor-specific CD8+ T-cells and knockdown in chimeric antigen receptor T-cells.

Main Results:

LARP4 selectively enhances translation of nuclear-encoded OXPHOS mRNAs in exhausted T-cells, leading to disrupted subunit balance and mitochondrial dysfunction.
Larp4 knockout in CD8+ T-cells reduced hypertranslation, restored mitochondrial function, mitigated exhaustion, and improved anti-tumor responses.
LARP4 knockdown in CAR T-cells prevented terminal exhaustion and enhanced therapeutic responses against both liquid and solid tumors.

Conclusions:

Translation dysregulation, mediated by LARP4, is a key determinant of T-cell dysfunction in solid tumors.
Targeting LARP4 represents a potential strategy to improve the long-term efficacy and persistence of adoptive T-cell therapies.