CCR7-PERK-CREB3L1 signaling mediates tumor-associated macrophages-derived SPP1 promotion of oral squamous cell carcinoma

Chemokine receptor type 7 (CCR7) is extensively implicated in the regulation of inflammatory signaling. Although CCR7 is frequently overexpressed in malignant epithelial cells, its immunomodulatory role in tumor-associated macrophages (TAMs) and its contribution to oral squamous cell carcinoma (OSCC) progression remain poorly defined. To investigate the functional relevance of CCR7 in TAMs, we establish a CCR7-deficient (Ccr7-/-) mouse model of OSCC. We find that loss of CCR7 in TAMs suppresses the malignant phenotype of OSCC cells and inhibits OSCC progression. We perform single-cell RNA sequencing to profile CCR7-dependent transcriptional changes in TAMs. This analysis identifies SPP1 as a key CCR7-regulated effector that promotes the malignant phenotype of OSCC cells. Consistent with this finding, in vitro assays confirm that TAM-derived SPP1 promotes the malignant phenotype of OSCC cells, whereas neutralization of SPP1 reverses OSCC progression. Mechanistically, CCR7 in TAMs regulates the transcription factor CREB3L1 via the PERK pathway, thus enhancing the expression of its downstream target gene SPP1. We further show that inhibition of the CCR7-CREB3L1 axis in TAMs significantly suppresses OSCC progression in vivo. These findings suggest that targeting the CCR7–CREB3L1 axis in TAMs may represent a promising therapeutic strategy for OSCC. Mechanistic characterization of a CCR7-PERKCREB3L1 signaling axis in tumor-associated macrophages reveals how macrophage-derived SPP1 contributes to oral squamous cell carcinoma progression.