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Objective Expression of CXC-chemokine receptor 4 (CXCR4) is associated with poor prognosis in colorectal cancer (CRC), metastasis and immune cell infiltration. Currently, only patients with metastatic CRC with mismatch repair deficient (dMMR) tumours (<10%) are eligible for immune checkpoint blockade (ICB).Methods and analysis 15 026 CRC tumour samples were analysed at Caris Life Sciences using whole-exome sequencing, whole-transcriptome sequencing and immunohistochemistry (IHC). This was a retrospective analysis in which all consecutive CRC cases between 2008 and 2023 with available molecular profiling and survival data were included. To elucidate the role of CXCR4 mRNA expression in the tumour microenvironment (TME) and response to ICB, CRC samples were stratified by high and low quartiles of CXCR4 mRNA expression levels and compared for molecular and clinical characteristics. Tumour mutational burden [TMB) and dMMR status were determined from DNA sequencing data. Immune cell infiltration was calculated from deconvolution of bulk RNA sequencing data. PD-L1 expression was determined by IHC stain intensity. Information for real-world survival and pembrolizumab treatment was obtained from the CODEai database using insurance claims-based data.Overall survival was calculated from date of either first specimen collection or treatment to last of healthcare contact with HR and p value calculated using the Cox proportional hazards model and log-rank test, respectively.Results Metastatic sites showed higher CXCR4 expression than primary tumours (22.7 vs 18.6 median transcripts per million [TPM], p<0.001). CXCR4 expression was lower in liver than non-liver metastases (21.2 vs 24.8 TPM, p<0.001). Median CXCR4 mRNA expression was positively associated with high TMB, dMMR and positive PD-L1 status. High CXCR4 expression was associated with tumours with higher infiltration of B cells and M1/M2 macrophages. High CXCR4 expression in the primary tumour was associated with worse prognosis (HR 0.92, 95% CI 0.86 to 0.99, p<0.02), regardless of dMMR status. In metastatic tumours, high CXCR4 mRNA expression correlated with improved survival (HR 1.12, 95% CI 1.04 to 1.20, p=0.003). Remarkably, high CXCR4 expression was associated with improved survival in all ICB-treated patients.Conclusion Correlation of high CXCR4 expression with changes in the TME and improved outcomes following ICB suggests its potential for selecting immunotherapeutic strategies in CRC.