Therapeutic vaccines for NSCLC: From mechanisms to clinical translation.

Despite advances in targeted therapy and immune checkpoint inhibitors (ICIs), durable disease control remains elusive for most patients with non-small cell lung cancer (NSCLC), particularly those with advanced-stage disease. Therapeutic cancer vaccines offer the potential for sustained immune surveillance by inducing tumor-specific effector and memory T-cell responses. However, their clinical benefits have been inconsistent to date. In advanced disease, rapid tumor progression, an immunosuppressive tumor microenvironment (TME), defective antigen presentation, and immune escape collectively impair the infiltration, persistence, and cytotoxic function of vaccine-induced T cells. These biological factors suggest that vaccine activity may depend on a therapeutic window characterized by lower tumor burden, preserved antigen presentation, and limited immunosuppression. Combination strategies with ICIs, chemotherapy, or radiotherapy are being investigated to increase antigen release and reduce TME-mediated immunosuppression. Vaccine development has also expanded beyond shared tumor-associated antigens to include personalized and shared tumor-specific antigens, as well as multi-epitope designs intended to improve immunogenicity and patient selection. Nonetheless, antigen heterogeneity, immune editing, manufacturing timelines, and the safety of combination regimens remain key translational challenges. Therapeutic vaccines may therefore be viewed as immunomodulatory agents whose long-term value in NSCLC will depend on antigen selection, treatment timing, and integration with multimodal therapy.