SPP1+ macrophages: A malignant macrophage subset in the colorectal cancer microenvironment revealed by single-cell sequencing

AbstractAccumulating single-cell studies suggest that SPP1 + macrophages are key players in the tumor microenvironment. However, a systematic investigation of SPP1 + macrophages in colorectal cancer (CRC) has not been conducted. A total of eight single-cell RNA-seq datasets and 16 bulk RNA-seq datasets were included in this study. On the basis of existing research, we propose the SPP1 + macrophage model paradigm, which can explain the clinical features and functional changes of macrophages in CRC better than the M1/M2 polarization theory. We identified four macrophage subsets from CRC myeloid cells: FCN1 + macrophages, C1QC + macrophages, SPP1 + macrophages, and MKI67 + macrophages. Inflammation, phagocytosis, malignancy, and proliferation were identified as the most prominent features related to each of the four macrophage subsets. Our results show that SPP1 + macrophages can serve as markers of CRC occurrence, progression, metastasis and a poor prognosis and exhibit enhanced transcription of genes associated with angiogenesis, epithelial-mesenchymal transition, glycolysis, hypoxia, and immunosuppressive signatures. CellPhoneDB analysis further indicated that SPP1 may mediate crosstalk between SPP1 + macrophages and other cells via the SPP1-CD44, SPP1-PTGER4 and SPP1-a4b1 complex axes. Additionally, our study suggests that SPP1 + macrophages are associated with the benefit of immune checkpoint blockade (ICB) therapy and that immunotherapy targeting SPP1 + macrophages is expected to improve the prognosis of CRC patients. Furthermore, anti-CSF1R treatment is more likely to preferentially deplete CSF1R-enriched C1QC + macrophages versus SPP1 + macrophages, which may account for the minimal effect of this monotherapy.