Life sciences · 2026
Targeting IGF2BP3-driven CSF1/CSF1R signaling disrupts the positive feedback loop between tumor cells and macrophages and inhibits HCC progression.
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Ji Xiaoying, Zhang Linran, Zhu Xiaoxiao, He Jinli, Ju Yaxin, Jin Congying, Ma Wanli, Kong Xiangbing, Guo Honghui, Yu Dianke, Zhao Kunming
Аннотация
AIMS: Hepatocellular carcinoma (HCC) remains a major global malignancy characterized by a complex tumor microenvironment (TME) and poor prognosis. Expansion and pro-tumoral polarization of tumor-associated macrophages (TAMs) are principal contributors to malignant progression, but the precise regulatory mechanisms underlying these interactions remain unclear.
MATERIALS AND METHODS: Publicly available HCC datasets and a DEN/CCl4-induced HCC mouse model assessed the clinical relevance and dynamic expression of IGF2BP3. Transcriptomic analyses of primary mouse hepatocytes, in vitro and in vivo loss-of-function assays, investigated its role in macrophage remodeling. Pharmacological blockade, RNA stability and RNA immunoprecipitation assays determined the involvement of CSF1/CSF1R axis and elucidated the mechanism underlying IGF2BP3 binding to and stabilization of CSF1 mRNA.
KEY FINDINGS: IGF2BP3 was markedly upregulated in blood and tumor tissues of HCC patients, and its high expression correlated with poor survival and increased macrophage infiltration. IGF2BP3 silencing potently suppressed macrophage recruitment and polarization toward a pro-tumoral phenotype by downregulating the CSF1/CSF1R signaling axis. Conversely, blockade of CSF1/CSF1R signaling abrogated IGF2BP3-driven macrophage recruitment and remodeling, disrupted the interaction between HCC cells and macrophages, and attenuated HCC cell malignant progression and migration. Mechanistically, IGF2BP3 directly binds to the 3'UTR of CSF1 mRNA, enhancing its stability in an m6A-independent manner and sustaining its secretion from HCC cells.
SIGNIFICANCE: Collectively, our findings reveal that IGF2BP3 drives HCC malignancy by establishing a reciprocal interaction between tumor cells and macrophages via the CSF1/CSF1R signaling pathway, highlighting that therapeutic targeting of this axis may disrupt tumor-macrophage crosstalk and improve therapeutic efficacy.
MATERIALS AND METHODS: Publicly available HCC datasets and a DEN/CCl4-induced HCC mouse model assessed the clinical relevance and dynamic expression of IGF2BP3. Transcriptomic analyses of primary mouse hepatocytes, in vitro and in vivo loss-of-function assays, investigated its role in macrophage remodeling. Pharmacological blockade, RNA stability and RNA immunoprecipitation assays determined the involvement of CSF1/CSF1R axis and elucidated the mechanism underlying IGF2BP3 binding to and stabilization of CSF1 mRNA.
KEY FINDINGS: IGF2BP3 was markedly upregulated in blood and tumor tissues of HCC patients, and its high expression correlated with poor survival and increased macrophage infiltration. IGF2BP3 silencing potently suppressed macrophage recruitment and polarization toward a pro-tumoral phenotype by downregulating the CSF1/CSF1R signaling axis. Conversely, blockade of CSF1/CSF1R signaling abrogated IGF2BP3-driven macrophage recruitment and remodeling, disrupted the interaction between HCC cells and macrophages, and attenuated HCC cell malignant progression and migration. Mechanistically, IGF2BP3 directly binds to the 3'UTR of CSF1 mRNA, enhancing its stability in an m6A-independent manner and sustaining its secretion from HCC cells.
SIGNIFICANCE: Collectively, our findings reveal that IGF2BP3 drives HCC malignancy by establishing a reciprocal interaction between tumor cells and macrophages via the CSF1/CSF1R signaling pathway, highlighting that therapeutic targeting of this axis may disrupt tumor-macrophage crosstalk and improve therapeutic efficacy.