TAMs-derived SPP1, regulated by HIF-1α/STAT3 signaling pathway, influences colorectal cancer malignant progression by activation of EMT via integrin αvβ3.

Liver metastasis of colorectal cancer (CRC) is characterized by a high recurrence rate after surgery, which may be related to the rerecruitment of residual tumor cells by other factors that promote cancer cell growth in the tumor microenvironment. Tumor-associated macrophages (TAMs), as key immune components, showed high expression of secretory phosphoprotein-1 (SPP1) at the site of liver metastasis in colorectal cancer patients. However, the factors and mechanisms driving the elevated expression of SPP1 in TAMs remain poorly understood, as do the potential effects of SPP1 on colorectal cancer progression. In this study, we investigated the factors that contributed to the high expression of SPP1 in TAMs and its role in promoting the M2 polarization of TAMs. Additionally, we examined the direct impact of SPP1 derived from TAMs on the malignant phenotype of colorectal cancer. The results showed that the two major characteristics of the tumor microenvironment-hypoxia and acidity-synergistically increased the expression of SPP1 in TAMs through the HIF-1α/STAT3 signaling pathway, Moreover, elevated SPP1 protein promoted the M2-like polarization of TAMs by reducing mitochondrial damage and affecting metabolic reprogramming. In addition, TAMs-derived SPP1 could directly influence the malignant progression of colorectal cancer by interacting with αvβ3 integrin through paracrine on the surface of cancer cells. Inhibiting HIF-1α involved in the regulation of SPP1 and blocking the direct action of SPP1 with cancer cells could effectively inhibit liver metastasis of CRC. These findings suggested that blocking the upstream signaling pathway of SPP1 or inhibiting its downstream target could be a promising therapeutic strategy to prevent or reduce liver metastasis recurrence in CRC.