Sustaining Antitumor Immunity: The Unmet Challenge of Durable T-Cell Responses in Cancer Vaccination

This narrative review examines therapeutic cancer vaccines, which have undergone a profound renaissance, transitioning from early peptide and dendritic cell-based formulations to next-generation mRNA platforms enabling personalized neoantigen targeting. Despite unprecedented successes—most notably the autogene cevumeran trial in pancreatic ductal adenocarcinoma achieving durable CD8+ T cell responses, with a model-estimated mean clonal lifespan of 7.7 years in a small phase I trial—a fundamental “durability paradox” persists: robust peripheral T cell responses frequently fail to translate into long-term clinical benefit. This review systematically examines the immunological basis of durable antitumor immunity, the clinical evidence supporting long-lived T cell responses, and the formidable barriers imposed by the tumor microenvironment (TME). We dissect how chronic antigen exposure, metabolic competition, and epigenetic reprogramming—particularly TOX-driven exhaustion—conspire to erode memory T cell pools. We then evaluate engineering strategies to enhance durability, including optimized antigen selection (neoantigens over TAAs), rational adjuvant selection (TLR9/CD40/STING agonists), sustained-release delivery systems (LNPs, polymeric depots), prime-boost scheduling, and combinatorial approaches with immune checkpoint inhibitors and TME modulators. Finally, we discuss emerging biomarkers (TCR clonality tracking, ctDNA dynamics) and future directions, including AI-driven multi-omics modeling and neoadjuvant vaccination. The convergence of compelling decade-scale durability data—from mRNA, UV1, and WT1 peptide vaccines—with next-generation engineering platforms suggests that cancer vaccines may evolve from short-term immune activators into long-term immune sentinels, provided that the dual challenges of T cell stemness preservation and TME immunosuppression are simultaneously addressed.