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

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.