Ciliary-Mitochondrial Crosstalk in Cancer: Mechanistic Links Between Primary Cilium Dysfunction and Mitochondrial Reprogramming in Tumor Progression and Metastasis

Primary cilia are microtubule-based sensory organelles that coordinate key oncogenic signaling pathways, including Hedgehog, Wnt, PDGF, and TGF-β. Mitochondria, traditionally viewed as bioenergetic hubs, also regulate redox balance, calcium homeostasis, apoptosis, and metabolic plasticity. Emerging evidence demonstrates that these organelles are functionally coupled, forming a bidirectional ciliary-mitochondrial axis that influences cancer progression and metastasis. Disruption of ciliogenesis, often through IFT88 or KIF3A loss, impairs mitochondrial oxidative phosphorylation and promotes a glycolytic, biosynthetic phenotype. Conversely, mitochondrial dysfunction, excessive reactive oxygen species (ROS), and altered dynamics feedback to regulate ciliary assembly and signaling. Key mechanistic nodes include calcium flux, AMPK-ULK1 signaling, ROS-mediated communication, and the recently identified NDUFAF2-ARMC9 bridge linking mitochondrial metabolism to ciliogenesis. This crosstalk converges on pathways that drive epithelial-to-mesenchymal transition, cancer stemness, migration, invasion, and therapeutic resistance. In the tumor microenvironment, hypoxia, nutrient deprivation, immune signaling, and extracellular vesicles further modulate this axis, contributing to metabolic heterogeneity and metastatic dissemination. Importantly, the relationship between cilia and cancer is context-dependent: cilia can be tumor-suppressive in some malignancies yet support oncogenic signaling in others. These insights suggest that targeting ciliary function, mitochondrial metabolism, or their intersection may offer novel therapeutic opportunities. This review synthesizes current evidence on ciliary-mitochondrial crosstalk, highlights unresolved mechanistic questions, and proposes an integrated framework for understanding how this organellar axis shapes cancer evolution and treatment response. We propose that integrated ciliary-mitochondrial signatures represent highly promising novel cancer biomarkers capable of predicting tumor plasticity, metastatic risk, and therapeutic response beyond conventional single-organelle or genomic markers.