2. Academic Validation
  3. Myeloid-lineage-specific membrane protein LRRC25 suppresses immunity in solid tumor and is a potential cancer immunotherapy checkpoint target

Myeloid-lineage-specific membrane protein LRRC25 suppresses immunity in solid tumor and is a potential cancer immunotherapy checkpoint target

  • Cell Rep. 2025 May 27;44(5):115631. doi: 10.1016/j.celrep.2025.115631.
Guorong Zhang 1,  Hanzhi Yu 1,  Jingjing Liu 1,  Ge Dong 1,  Zhigang Cai 2
Affiliations

Affiliations

  • 1 Tianjin Key Laboratory of Inflammatory Biology, Department of Pharmacology, School of Basic Medical Science, Tianjin Medical University, Tianjin, China; State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China.
  • 2 Tianjin Key Laboratory of Inflammatory Biology, Department of Pharmacology, School of Basic Medical Science, Tianjin Medical University, Tianjin, China; State Key Laboratory of Experimental Hematology, Tianjin Medical University, Tianjin, China; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China; Department of Bioinformatics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China; Department of Hematology, Tianjin Medical University Tianjin General Hospital, Tianjin, China; Department of Rheumatology and Immunology, Tianjin Medical University Tianjin General Hospital, Tianjin, China. Electronic address: us36zcai@tmu.edu.cn.
PMID: 40279244 DOI: 10.1016/j.celrep.2025.115631
Abstract

Leucine-rich repeat containing 25 (LRRC25), a type I membrane protein, is specifically expressed in myeloid cells including neutrophils and macrophages. The anti-inflammatory role of LRRC25 was suggested in a few pathogenic models. However, its role in Cancer immunity has not been interrogated. Here, we demonstrate that LRRC25 is robustly expressed in tumor-associated macrophages (TAMs). Lrrc25 deficiency in the tumor microenvironment (TME) suppresses growth of multiple murine tumor models by reprogramming TAMs toward an anti-tumor phenotype and thereby enhancing infiltration and activation of CD8+ T cells. The Nox2-ROS-Nlrp3-Il1β pathway is elevated in Lrrc25-deficient TAMs. Furthermore, a human myeloid cell line or mice with loss of Lrrc25 appear normal, indicating that LRRC25 is a safe immune target. Our results suggest that as an unappreciated immune checkpoint for tumor immunotherapy, the myeloid-specific membrane protein LRRC25 orchestrates the activity of TAMs via the canonical Nlrp3-IL1β inflammatory pathway and influences CD8+ T cell chemotaxis to the TME.

Keywords

CP: Cancer; CP: Immunology; LRRC25; cancer immunotherapy; membrane protein; tumor microenvironment; tumor-associated macrophages.

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