Abstract
Background: Tumor-associated macrophages (TAMs) play a pivotal role in facilitating tumor immune escape in colorectal cancer (CRC). C-type lectin Dendritic Cell-Specific ICAM-Grabbing Nonintegrin (DC-SIGN) is variably expressed in TAMs in tumor tissues. However, its role in CRC progression remains poorly defined. Methods: We analyzed The Cancer Genome Atlas (TCGA) data and an independent CRC cohort to evaluate the prognostic significance of DC-SIGNhigh TAMs. Immunofluorescence and flow cytometry were used to characterize DC-SIGN expression in CRC tissues. RNA sequencing and bioinformatics analyses were performed on sorted DC-SIGNhigh and DC-SIGNlow TAMs. Functional assays using THP-1-derived macrophages and primary TAMs were conducted to examine how DC-SIGN regulates PD-L1 expression via the transcription factor BCL-3. Results: DC-SIGN was specifically expressed in TAMs within CRC tissues and was associated with increased stromal and immune cell infiltration. DC-SIGN expression correlated with worsened prognosis in CD8high, but not CD8low, patients with CRC across two independent cohorts, and served as an independent predictor of unfavorable survival in CD8high CRC. Transcriptomic profiling revealed that DC-SIGNhigh TAMs exhibited distinct immune-related pathways, including marked upregulation of PD-L1 and PD-L1 immune checkpoint pathway. Mechanistically, Lewisx-ligated DC-SIGN upregulated PD-L1 expression at both mRNA and protein levels through BCL-3, which directly bound to the PD-L1 promoter. Conclusion: The DC-SIGN/BCL-3 axis in TAMs drives PD-L1 expression and contributes to CRC immune evasion. Targeting DC-SIGN+ TAMs may represent a promising therapeutic strategy to reprogram the tumor microenvironment (TME) and improve the efficacy of immunotherapy in CRC.