Lung cancer vaccines to enhance immune checkpoint inhibitor therapy: evidence and future perspectives

Abstract Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of lung cancer over the past decade, markedly improving antitumor responses, overall survival, and quality of life. However, durable clinical benefit is achieved in only a subset of patients, and resistance to ICIs remains a major clinical challenge. Mechanistically, resistance arises from multiple, often overlapping processes, including inadequate tumor antigen presentation, dysfunctional T-cell priming and expansion, and the presence of physical and immunosuppressive barriers within the tumor microenvironment that limit immune cell infiltration and effector function. Cancer vaccines have re-emerged as a rational immunotherapeutic strategy to overcome these obstacles by inducing de novo or amplifying pre-existing tumor-specific immune responses, thereby enhancing long-term immunological memory while maintaining a favorable safety profile. Advances in antigen discovery, neoantigen prediction, and vaccine platforms have accelerated the development of both personalized and off-the-shelf neoantigen vaccines. Although personalized neoantigen vaccines have gained considerable attention following the success of mRNA-based COVID-19 vaccines, off-the-shelf approaches offer advantages in scalability, cost, and manufacturing timelines, facilitating broader clinical implementation. Accumulating preclinical and clinical evidence suggests that cancer vaccines are more effective in the adjuvant setting than in the metastatic setting, where high tumor burden and an immunosuppressive tumor microenvironment constrain vaccine-induced immune responses. Consistent with their limited efficacy as monotherapy, contemporary clinical trials increasingly evaluate cancer vaccines in combination with ICIs or other immunotherapeutic agents to enhance T-cell activation, reverse immune suppression, and restore antitumor immunity. This review synthesizes current mechanistic insights, highlights ongoing clinical efforts, and discusses future directions for rational cancer vaccine development in lung cancer, with an emphasis on overcoming resistance to ICI.