Tumor-derived CCL15 regulates RNA m6A methylation in cancer-associated fibroblasts to promote hepatocellular carcinoma growth

Hepatocellular carcinoma (HCC) is a lethal malignancy characterized by rapid growth. The interaction between tumor cells and cancer-associated fibroblasts (CAFs) significantly influences HCC progression. CCL15, a CC chemokine family member, is predominantly expressed in HCC and strongly correlates with tumor size, indicating its critical role in HCC growth. However, previous studies suggest that CCL15 does not directly stimulate cancer cell proliferation. The specific role and mechanism of CCL15 in HCC proliferation remain unknown. Here, we identified that CCL15 was predominantly overexpressed by HCC cells through single-cell RNA sequencing data and immunofluorescence. We discovered that CCL15 promotes HCC growth by stimulating the crosstalk between HCC cells and CAFs via CCR1 signaling, as evidenced by co-culture assays, organoid models, and allograft models. Mechanistically, CCL15 induced the expression of FTO in CAFs through the STAT3 pathway. By m6A sequencing and RNA sequencing, we found that CEBPA mRNA, a transcription factor regulating CXCL5 expression, was a target of FTO. CXCL5, secreted by CAFs, activated the CXCR2 receptor on HCC cells and enhanced their proliferation. Notably, we found that interfering with CCL15 signaling using a neutralizing antibody attenuated HCC growth in heterotypic co-injection and patient-derived xenograft murine models. Finally, CXCL5 also upregulated CCL15 expression in HCC cells by modulating P53 expression through MDM2, forming a positive feedback loop. Our study unveiled CCL15 as a key mediator in HCC progression, facilitating communication between HCC cells and CAFs. This highlights a novel regulatory axis in HCC and suggests that targeting CCL15 could be a potential therapeutic strategy.