Telomere maintenance meets cancer metabolism: Mechanistic insights and clinical opportunities

Telomere maintenance and metabolic reprogramming are two fundamental and interdependent hallmarks of cancer. While telomerase reactivation or the alternative lengthening of telomeres (ALT) enables cancer cells to evade replicative senescence, metabolic rewiring sustains the bioenergetic and biosynthetic demands of uncontrolled proliferation. Emerging evidence indicates a dynamic bidirectional relationship between telomere dynamics and metabolism, influenced by the tumor microenvironment (TME), inflammatory stress, and hypoxia. This review provides a comprehensive, cancer-type-specific analysis of telomere-metabolism crosstalk across glioblastoma, hepatocellular carcinoma, colorectal cancer, breast and prostate cancers, gastric cancer, and hematologic malignancies. We highlight the distinct metabolic phenotypes associated with telomerase activation or ALT engagement and examine how these pathways converge on mitochondrial function, redox balance, and chromatin remodeling. Furthermore, we discuss emerging therapeutic strategies, including the development of telomerase inhibitors, metabolic modulators (e.g., glutaminase and fatty acid synthesis inhibitors), and combination regimens currently in clinical trials. Novel biomarker-based approaches for patient stratification-such as TERT promoter mutations, ALT activity signatures, and metabolomic flux-are also explored. Understanding the intricate interplay between telomere maintenance and metabolism offers a promising axis for next-generation precision oncology.