The Central Role of HLA Class II-Restricted Helper Neoantigen Vaccines in Cancer Immunotherapy

The discovery of neoantigens and their application in cancer vaccines have brought about a paradigm shift in cancer immunotherapy, similar to the way in which immune checkpoint inhibitors redefined therapeutic strategies for cancer treatment. Early neoantigen vaccine approaches primarily focused on eliciting HLA class I-restricted CD8⁺ cytotoxic T lymphocyte (CTL) responses, whereas it has become clear that such strategies alone may be insufficient to establish durable and effective antitumor immunity. Increasing attention has therefore shifted toward HLA class II-restricted neoantigens ("helper neoantigens") that activate tumor-specific CD4⁺ helper T cells. Recent studies have revealed that neoantigen-reactive CD4⁺ helper T cells play a central role in coordinating antitumor immune responses through dendritic cell licensing, thereby sustaining CD8⁺ CTL function, preventing T-cell exhaustion, and promoting the generation of long-lived memory T cells. These findings have highlighted the pivotal role of helper neoantigens in shaping vaccine efficacy. In this review, we discuss the mechanistic basis underlying the contribution of helper neoantigens to tumor immunity and highlight recent advances in the real-world application of helper neoantigen-based vaccine strategies.