The Role of CCR1 as a decisive factor for immune response activation versus suppression phenotypes in gastric cancer.

Abstract

BACKGROUND: Chemokine receptor 1 (CCR1), a regulator of immune cell migration, has been implicated in various cancers but remains poorly characterized in gastric cancer's immune microenvironment. This study aimed to investigate whether CCR1 promotes or suppresses tumor progression in gastric cancer. METHODS: Utilize transcriptomic analysis to investigate the role of CCR1 in gastric cancer, and employed clinical data to examine the correlation between CCR1 expression and patient survival as well as pathological features. In vivo models with CCR1-knockout mice and macrophage depletion experiments validated functional roles, while Western blotting and qRT-PCR explored The pathways and signaling. RESULTS: Following patient stratification based on optimal cut-off values, Kaplan-Meier survival analysis demonstrated that patients with high CCR1 expression had longer survival times. Single-cell and spatial transcriptomics analyses revealed that CCR1 is predominantly expressed on macrophages. Immunofluorescence assays showed greater co-localization of CCR1 and CD68 in gastric cancer tissues compared to adjacent normal tissues, confirming CCR1 expression in macrophages. In vivo experiments demonstrated that CCR1 deficiency increased tumor growth by reducing T cell infiltration, an effect that was abrogated by macrophage depletion. Mechanistically, CCR1 activates the NF-κB and MAPK pathways in macrophages to upregulate CXCL9 and CXCL10, thereby promoting T cell recruitment to the tumor microenvironment. CONCLUSIONS: CCR1 modulates T cell distribution via CXCL9/CXCL10, suggesting potential therapeutic directions.