mRNA and DNA-Based Vaccines in Genitourinary Cancers: A New Frontier in Personalized Immunotherapy

Abstract

Genitourinary (GU) cancers, including prostate, bladder, and renal cancers, represent a significant burden on global health. Conventional treatments, while effective in certain contexts, face limitations due to tumor heterogeneity, therapeutic resistance, and relapse. Recent advances in cancer immunotherapy, particularly in the development of personalized mRNA and DNA-based vaccines, have opened new avenues for precise and durable antitumor responses. These vaccines are being developed to leverage neoantigen identification and next-generation sequencing technologies, with the goal of tailoring immunotherapeutic interventions to individual tumor profiles. mRNA vaccines offer rapid, non-integrative, and scalable, with encouraging results reported in infectious diseases and early-phase cancer trials. DNA vaccines, known for their stability and ease of modification, show promise in generating robust cytotoxic T-cell responses. This review discusses the current landscape, preclinical findings, and ongoing clinical trials of mRNA and DNA-based vaccines in GU cancers, highlighting delivery technologies, combination strategies with immune checkpoint inhibitors, and future challenges, including tumor immune evasion and regulatory hurdles. Integrating immunogenomics and artificial intelligence into vaccine design is poised to further enhance precision in cancer vaccine development. As GU malignancies remain a leading cause of cancer-related morbidity and mortality, mRNA and DNA vaccine strategies represent a promising and rapidly evolving area of investigation in oncology.

Keywords: DNA vaccines; bladder cancer; genitourinary cancer; immunotherapy; mRNA vaccines; neoantigens; personalized cancer vaccine; prostate cancer; renal cell carcinoma; tumor microenvironment.

Figure 1

Overview of Genitourinary Cancers and Emerging Nucleic Acid Vaccine Therapies. This figure depicts the three major genitourinary (GU) cancers: prostate, bladder, and kidney cancer, with approximate global incidence rates. Common challenges faced by these cancers include tumor heterogeneity, immune evasion, and resistance to therapies such as androgen deprivation therapy (ADT), chemotherapy, and checkpoint inhibitors. Preclinical models combined with next-generation sequencing (NGS) and bioinformatics enable the identification of tumor neoantigens for the development of nucleic acid vaccines (mRNA and DNA), which leverage neoantigen targeting and personalized vaccine design to improve clinical outcomes.

Figure 2

Overview of Antigen Presentation and T-cell Activation Pathway in Cancer Vaccination. This figure illustrates the key steps involved in the immune response triggered by mRNA or DNA-based cancer vaccines. After administration, the nucleic acid vaccine is taken up by antigen-presenting cells (APCs), such as dendritic cells, which translate the genetic material into tumor-associated antigens. These antigens are processed into peptides and loaded onto major histocompatibility complex (MHC) class I and II molecules. Peptide–MHC complexes are then presented on the surface of APCs to prime and activate CD8⁺ cytotoxic T lymphocytes (via MHC I) and CD4⁺ helper T cells (via MHC II). Activated CD8⁺ T cells recognize and kill tumor cells expressing the same antigen. However, the immune response can be negatively regulated by immunosuppressive mechanisms, including regulatory T cells (Tregs) and immune checkpoint molecules (e.g., PD-1/PD-L1 and CTLA-4), which may limit the efficacy of the vaccine-induced antitumor response.

Figure 3

Mechanistic Comparison of mRNA and DNA Cancer Vaccines. mRNA vaccines are translated in the cytoplasm after uptake by antigen-presenting cells, directly triggering T-cell responses. DNA vaccines require nuclear entry for transcription before antigen expression and presentation. Both platforms ultimately induce antigen-specific CD4⁺ and CD8⁺ T-cell responses.

Figure 4

Personalized Cancer Vaccine Development Workflow. This schematic outlines the sequential process for developing personalized mRNA and DNA-based cancer vaccines. It begins with tumor sample acquisition and next-generation sequencing (NGS) to identify somatic mutations. Artificial intelligence (AI) algorithms are then used to predict immunogenic neoepitopes, which are selected for inclusion in customized vaccine constructs. After synthesis, the vaccine is administered to the patient, followed by monitoring of antigen-specific immune responses. The workflow shown is tailored for genitourinary cancer vaccine development.

Figure 5

Barriers to Effective Vaccination in GU Cancers. Major immune and translational challenges in genitourinary cancer vaccine development include immunosuppressive cellular environment, poor delivery to antigen-presenting cells, neoantigen variability and clonal escape, difficulty in stratifying responders, weakly immunogenic antigens, and regulatory or production-related delays.