Leader cells promote immunosuppression to drive ovarian cancer progression in vivo.

Abstract

Over 75% of patients with ovarian cancer present with late-stage disease, often accompanied by extensive metastasis. The metastatic cascade is driven by a sub-population of transcriptionally plastic cells known as "leader cells" (LCs), which play a critical role in collective invasion yet remain poorly understood. LCs are marked by the expression of keratin-14 (KRT14), which determines their migratory and invasive capacity in ovarian cancer. This study demonstrates that KRT14+ LCs promote tumor progression through immunosuppression and immune privilege in vivo. In the ID8 syngeneic epithelial ovarian cancer mouse model, tumor-specific loss of KRT14+ LCs impairs tumor progression and metastatic spread without affecting cellular proliferation. Immune profiling shows reduced immunosuppressive regulatory T cells (Tregs) and M2 macrophages and improved CD8⁺ T cell/Treg ratios in LC knockout (LC^KO) mice. Conversely, forced LC overexpression accelerates metastasis and increases the secretion of immunosuppressive chemokines, such as CCL22 and CCL5, highlighting the role of KRT14+ LCs in immune suppression and metastatic progression.