Cancer-associated mitochondrial homeostasis disrupted and retrograde signaling activated.

This review discusses mitochondrial homeostasis disrupted and retrograde signaling activated in oncogenesis and cancer progression. We summarize mitochondrial alterations and dysfunction in cancer, including mitochondrial DNA mutations, copy number alterations, dynamics changes and abnormalities of mitochondria enzymes in cancer. Furthermore, we discuss the findings on the main molecular mechanisms and roles of mitochondrial retrograde signaling pathways networks, such as reactive oxygen species (ROS), unfolded protein response (mtUPR), calcium and other retrograde signaling on cancer progression. Dysfunctional mitochondria induced retrograde signaling can lead to changes in gene expression. Tumor cells intimidate mitochondrial regulatory pathways to support tumor growth. Looking forward, we highlight critical knowledge gaps, including the need to decipher the spatiotemporal dynamics of retrograde signals, the context‑dependent dual roles of mitochondrial stress responses, and the integration of multi‑omics data to identify predictive biomarkers. We also discuss emerging therapeutic strategies that target mitochondrial retrograde signaling, such as small‑molecule modulators of mitochondrial calcium uniporter, ROS‑scavenging nanomedicines, and combination regimens with immune checkpoint inhibitors. Mitochondrial retrograde signaling might be served as a potential target for new therapeutic interventions in cancers, and future research should focus on translating these mechanistic insights into clinically actionable approaches.