Mechanisms of telomere dysfunction in cancer from genomic instability to therapy: A review

Telomeres are critical nucleoprotein structures that safeguard chromosome ends from degradation and fusion, thereby ensuring genomic stability. Without proper maintenance, telomeres progressively shorten with each cell division, leading to dysfunction and triggering chromosomal instability. This dysfunction is a significant driver of tumorigenesis, primarily by facilitating genetic alterations such as aneuploidy, gene amplifications, and chromosomal rearrangements. Cancer cells bypass cellular aging by activating mechanisms like telomerase reactivation or the Alternative Lengthening of Telomeres (ALT) pathway to maintain telomere length. This review explores the mechanisms by which telomere dysfunction contributes to genomic instability and cancer progression, including telomere shortening, breakage-fusion-bridge (B/F/B) cycles, and the ALT pathway. Additionally, it addresses the therapeutic potential of targeting telomere maintenance, highlighting current strategies like telomerase and ALT inhibitors. However, developing telomere-based therapies presents challenges, including resistance mechanisms, off-target effects, and potential impacts on normal stem cells. Emerging research areas such as the development of biomarkers and combination therapies offer promising directions for overcoming these challenges. Understanding telomere dynamics provides novel opportunities to exploit cancer cell vulnerabilities and advance treatment strategies.