Therapeutic cancer vaccines: development, challenges, and future perspectives.

Therapeutic cancer vaccines are designed to induce tumor-specific immunity and durable antitumor surveillance. However, their clinical efficacy remains limited by antigen heterogeneity, defective antigen presentation, immune exhaustion, and immunosuppression within the tumor microenvironment (TME). Advances in sequencing, immunopeptidomics, artificial intelligence (AI)-assisted neoantigen prioritization, nucleic acid engineering, dendritic cell (DC) biology, and combination therapy have shifted the field from empirical antigen exposure toward mechanism-guided vaccine design. This review outlines the historical development of therapeutic cancer vaccines, neoantigen identification strategies, and recent progress in DNA, RNA, peptide, cellular, and viral vaccine platforms. Key mechanisms shaping vaccine response and resistance are also discussed, including pattern-recognition receptor (PRR) signaling, dendritic cell-mediated antigen presentation, T-cell effector and memory differentiation, metabolic adaptation, epitope spreading, and TME remodeling. Future therapeutic cancer vaccines should be developed as integrated immunological systems that coordinate antigen discovery, precise delivery, innate immune calibration, memory maintenance, and local immune suppression reversal to achieve reproducible clinical benefit.