The primary cilium dynamics in cancer progression: a central regulator of chemoresistance and metastatic behavior

Primary cilia are integrative sensory organelles that function as spatially confined hubs for both oncogenic signaling and tumor-suppressive signaling in cancer. Early oncogenic events, including KRAS activation and EZH2-mediated epigenetic repression, actively silence ciliogenesis, increase spatial constraints on key pathways and facilitate malignant transformation across several tumor types such as pancreatic, breast, renal, melanoma, and glioblastoma. However, under therapeutic, metabolic, or genotoxic stress, cancer cells can reassemble primary cilia via the DNA damage response (DDR), autophagy, and related mechanisms, using the ciliary compartment to engage survival pathways, acquire chemoresistance, and remodel their metastatic behavior. In some contexts, restored cilia promote the epithelial–mesenchymal transition, invasion, and dissemination, whereas in others, persistent deciliation sustains nuclear β‑catenin signaling and supports metastatic outgrowth, underscoring the context‑dependent nature of ciliary functions. This review synthesizes current evidence on how dynamic gain and loss of primary cilia orchestrate therapeutic resistance and metastatic progression and surveys emerging strategies to pharmacologically modulate ciliary structure and signaling. Understanding ciliary status as a dynamic biomarker and therapeutic vulnerability may enable cilia-directed precision oncology and more rational stratification of patients for cilia-targeted interventions.