GTSF1 promotes stemness in uterine carcinosarcoma through CCL1-mediated M1 macrophage aggregation.

Abstract

Uterine carcinosarcoma (UCS), a high-grade endometrial carcinoma, is a rare but increasingly prevalent malignant gynecologic neoplasm, now accounting for over 5% of endometrial cancers and associated with a characteristically poor prognosis. In this study, we demonstrate that elevated expression of GTSF1 is significantly correlated with reduced disease-free survival (DFS) in UCS patients and promotes enhanced invasive, migratory, and stem-like phenotypes in tumor cells. Mechanistically, we show that GTSF1 drives tumor progression via activation of CCL1, which induces chemotaxis of M1 macrophages toward malignant cells and subsequent IL-6 secretion, thereby amplifying cancer stemness. Multiplex immunohistochemical analysis revealed spatial co-localization and positive correlations among GTSF1, CCL1, and M1 macrophage infiltration in UCS tissue specimens. In vitro co-culture experiments further confirmed that GTSF1-mediated CCL1 expression promotes M1 macrophage recruitment and IL-6 production, shaping an immune-permissive microenvironment that supports metastatic progression and maintenance of tumor stemness. This comprehensive investigation highlights actionable therapeutic targets within both tumor cells and their immune niche, offering translational insights for the development of multimodal treatment strategies against this aggressive malignancy.