The role of therapeutic cancer vaccines in the modern immunotherapy era: State of the art with recent progress and future challenges.

Therapeutic cancer vaccines represent a promising frontier in precision oncology, aiming to elicit durable and tumor-specific immune responses. Recent advances in nucleic acid-based platforms, particularly mRNA and DNA vaccines, have accelerated clinical translation, especially following the success of mRNA vaccines against SARS-CoV-2. These innovations have enabled improved antigen delivery, immunogenicity, and flexibility through structural modifications such as self-amplifying or chemically modified mRNAs. In parallel, peptide-based vaccines have evolved through the incorporation of long synthetic peptides and the identification of tumor-specific neoantigens. Other strategies include dendritic cell-based vaccines and whole tumor cell approaches. Neoantigen vaccines have demonstrated a favorable safety profile and the ability to elicit robust CD4⁺ and CD8⁺ T cell responses across various cancer types and disease stages. Optimal efficacy, however, depends on careful antigen selection, favoring clonal, driver mutations, and timely administration, ideally in early-stage or minimal residual disease settings to circumvent immune evasion and systemic immunosuppression. The tumor microenvironment (TME) critically shapes vaccine responsiveness, influenced by both tumor-intrinsic factors (e.g., antigen presentation defects, HLA loss) and extrinsic immunosuppressive cells. High tumor mutational burden and inflamed TMEs correlate with stronger responses, but encouraging outcomes have also been observed in "cold" tumors. Combining vaccines with ICIs, chemotherapy, or cytokine therapies can enhance efficacy by overcoming immune resistance. Optimizing clinical trial design and ensuring cost-effectiveness will be essential for translating personalized cancer vaccines into routine clinical practice.