Tumour-derived SAA1 reprogrammes macrophages to promote CXCL1-mediated metastasis in Ovarian Cancer

Patients with advanced high-grade serous ovarian carcinoma (HGSOC) often experience extremely poor prognoses due to extensive peritoneal metastases, yet the underlying driving mechanisms remain unclear. This study reveals that serum amyloid A1 (SAA1) is markedly upregulated in late-stage HGSOC and is closely associated with poor prognosis and distant metastasis. These findings were validated through both single-cell RNA sequencing and clinical specimen analyses. Surprisingly, SAA1 does not directly promote tumour cell proliferation or migration. Instead, it reshapes the immunosuppressive tumour microenvironment by activating FPR2⁺ tumour-associated macrophages (TAMs). Mechanistically, the SAA1-FPR2 signalling axis triggers the JAK2/STAT3 pathway in macrophages, enhancing the transcription and secretion of CXCL1. This, in turn, induces epithelial-mesenchymal transition (EMT) in tumour cells and endows them with greater metastatic potential. Animal models further confirmed that SAA1 knockdown, macrophage depletion, or CXCL1 blockade all significantly suppressed peritoneal dissemination. Collectively, this study identifies a novel SAA1-TAM-CXCL1 immune-inflammatory signalling axis, elucidates its critical role in ovarian cancer metastasis, and provides a robust theoretical foundation for the development of innovative anti-metastatic therapeutic strategies. KEY POINTS: A distinct SAA1-enriched tumour cell subset with metastasis-associated features is identified in ovarian cancer. Tumour-derived SAA1 reprograms TAM through FPR2-mediated JAK2-STAT3 signalling to induce an immunosuppressive phenotype. The SAA1-TAM-CXCL1 axis facilitates metastatic progression in ovarian cancer.