Targeting Telomerase in Cancer: Vaccine-Based Strategies, Clinical Evidence, and Synergy with Immunotherapy

With each replication cycle, telomeres shorten. Telomerase can slow or reverse the rate of telomere shortening. In the era of cancer immunotherapy, telomerase is a promising tumor-associated antigen due to its widespread and specific expression in cancer cells and its strong immunogenicity. Interestingly, telomerase-based vaccines eradicate telomerase-expressing cancer cells by increasing antigen-specific T-cell responses rather than by directly inhibiting telomerase enzymatic activity as telomerase inhibitors function. To support this, telomerase-based vaccines, including DNA, mRNA, peptide-, and cell-based vaccines, have been evaluated in clinical settings to elucidate their molecular mechanisms of action. The aim of this review is to present the clinical effectiveness of telomerase vaccines alone or in combination with immunotherapy. In particular, the therapeutic effectiveness of telomerase vaccines is influenced by the tumor microenvironment and can be substantially increased by combining them with immune checkpoint inhibitors. To further optimize telomerase-based vaccines, we discuss translational challenges and highlight the need for further optimization.