Telomerase reverse transcriptase (TERT) is a key component of telomerase, which is abnormally activated in most cancers, enabling cells to escape senescence. TERT is regulated by various pathways, including transcriptional factors and post-translational modifications (PTMs), leading to its ectopic expression at the transcriptional and protein levels. TERT interacts with co-factors that influence its regulation in different cancers. This review focuses on TERT regulators and their downstream functions in cancer. Understanding these mechanisms can aid in developing cancer treatments targeting telomerase and cell senescence. TERT is involved in telomere maintenance by regulating telomerase activity and assembling with telomere-binding proteins. It also influences various aspects of the tumor microenvironment, including angiogenesis, EMT, and immune response. Small molecule inhibitors and TERT vaccines are under investigation as potential therapeutic targets. TERT's structure includes four motifs: the telomerase essential N-terminal (TEN) domain, the TERT RNA-binding domain (TRBD), the reverse transcriptase (RT) domain, and the C-terminal extension (CTE). These domains interact with telomerase RNA (hTR) and other proteins to regulate telomerase function. TERT is regulated by various PTMs, including phosphorylation, ubiquitination, and SUMOylation, which affect its stability, localization, and activity. TERT promoter mutations are common in various cancers and lead to TERT overexpression. These mutations are associated with increased telomerase activity and are linked to poor prognosis in some cancers. TERT is also regulated by transcription factors such as GABP and Sp1, which influence its expression through the MAPK signaling pathway. TERT plays non-canonical roles in cancer, including DNA repair, gene transcription, and ubiquitin-proteasomal function. It influences the tumor microenvironment by affecting angiogenesis, EMT, and immune response. TERT is recognized by the immune system and can be targeted by vaccines. Current and future pharmacological strategies targeting TERT or telomerase include small molecule inhibitors and vaccines. These approaches aim to inhibit telomerase activity and induce telomere dysfunction, leading to cancer cell death. However, challenges remain in terms of drug safety and efficacy. In conclusion, TERT is a critical regulator of telomerase activity and cancer progression. Understanding its regulation and functions can lead to the development of novel cancer therapies targeting telomerase and cell senescence. Further research is needed to improve the safety and effectiveness of these treatments.Telomerase reverse transcriptase (TERT) is a key component of telomerase, which is abnormally activated in most cancers, enabling cells to escape senescence. TERT is regulated by various pathways, including transcriptional factors and post-translational modifications (PTMs), leading to its ectopic expression at the transcriptional and protein levels. TERT interacts with co-factors that influence its regulation in different cancers. This review focuses on TERT regulators and their downstream functions in cancer. Understanding these mechanisms can aid in developing cancer treatments targeting telomerase and cell senescence. TERT is involved in telomere maintenance by regulating telomerase activity and assembling with telomere-binding proteins. It also influences various aspects of the tumor microenvironment, including angiogenesis, EMT, and immune response. Small molecule inhibitors and TERT vaccines are under investigation as potential therapeutic targets. TERT's structure includes four motifs: the telomerase essential N-terminal (TEN) domain, the TERT RNA-binding domain (TRBD), the reverse transcriptase (RT) domain, and the C-terminal extension (CTE). These domains interact with telomerase RNA (hTR) and other proteins to regulate telomerase function. TERT is regulated by various PTMs, including phosphorylation, ubiquitination, and SUMOylation, which affect its stability, localization, and activity. TERT promoter mutations are common in various cancers and lead to TERT overexpression. These mutations are associated with increased telomerase activity and are linked to poor prognosis in some cancers. TERT is also regulated by transcription factors such as GABP and Sp1, which influence its expression through the MAPK signaling pathway. TERT plays non-canonical roles in cancer, including DNA repair, gene transcription, and ubiquitin-proteasomal function. It influences the tumor microenvironment by affecting angiogenesis, EMT, and immune response. TERT is recognized by the immune system and can be targeted by vaccines. Current and future pharmacological strategies targeting TERT or telomerase include small molecule inhibitors and vaccines. These approaches aim to inhibit telomerase activity and induce telomere dysfunction, leading to cancer cell death. However, challenges remain in terms of drug safety and efficacy. In conclusion, TERT is a critical regulator of telomerase activity and cancer progression. Understanding its regulation and functions can lead to the development of novel cancer therapies targeting telomerase and cell senescence. Further research is needed to improve the safety and effectiveness of these treatments.