Spatiotemporal control of mitoribosome-mediated metabolic reprogramming in cancer: implications for heterogeneity and therapeutic targeting

Abstract

Mitochondrial ribosomes (mitoribosomes), particularly mitochondrial ribosomal subunit proteins (MRPS), are emerging as contributors to cancer metabolic reprogramming. Rather than static components of mitochondrial translation, MRPS exhibit pronounced spatiotemporal heterogeneity that shapes tumor metabolic plasticity and therapeutic response. This review systematically summarizes evidence that MRPS functions are dynamically regulated across tumor progression and spatial microenvironments. Temporally, MRPS mediate metabolic switching between oxidative phosphorylation (OXPHOS) and glycolysis, contributing to metabolic adaptation, treatment resistance, and tumor evolution. Spatially, MRPS display context-dependent functions across tumor regions, cancer types, and metabolic microenvironments, thereby contributing to intratumoral metabolic diversity. We further highlight that MRPS-associated metabolic plasticity is linked with lactate metabolism and hypoxia-inducible factor (HIF) signaling, forming feedback networks associated with tumor growth, immune escape, and therapy resistance. This spatiotemporal regulatory axis challenges the traditional static view of mitochondrial dysfunction in cancer. Targeting MRPS-associated metabolic adaptation may provide therapeutic opportunities beyond the traditional Warburg framework. Emerging technologies, including lactate-sensitive nanoprobes, reactive oxygen species (ROS)-responsive delivery systems, and MRPS-related imaging platforms, may support metabolic monitoring and targeted therapeutic intervention. Collectively, this framework links mitochondrial translation with tumor metabolism and microenvironmental regulation, providing additional insight into metabolic adaptation in cancer.