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Mariella Careaga
Finding effective ways to treat different types of cancer has been a long-standing goal for scientists all over the world. In this quest, many have turned their attention to vaccines. Originally created to fight microbes that cause infections, the vaccine’s ability to stimulate immune responses specifically against certain antigens has been recognized as a promising therapeutic instrument in the battle with cancer (1).
As we previously discussed, the idea of activating a person’s immune system to search and destroy cancer cells is not new (2). However, advances in how we look for and select antigens, as well as new platforms and delivery methods, are paving the way for developing more specific and potent therapeutic cancer vaccine options.
What are therapeutic cancer vaccines and how do they work?
Therapeutic cancer vaccines are medical products designed to treat a type of cancer after it occurs. As with other vaccines, they work by training the immune system to recognize and defend a person’s body against a threat — in this case, abnormal cells that grow uncontrollably, spread, and give rise to malignant tumors.
To teach our immune system how to search for and destroy cancerous cells, vaccines expose immune cells called T cells to specific molecules known as antigens. Primarily proteins or peptides, antigens act as markers that help the immune system differentiate between what is self and what is not, and then initiate a response that aims to eliminate the foreign entity.
Two types of tumor antigens can be used to make a cancer vaccine: tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs). TSAs are only found in cancer cells and result from malignant mutations or the expression of viral elements. The most commonly targeted TSAs are neoantigens. Produced by mutations in the tumor’s DNA, neoantigens are considered highly immunogenic, meaning they can induce a strong immune response. Due to their great variability, neoantigens are unique to each patient, making them ideal targets for personalized cancer vaccines (3).
In contrast, TAAs hold promise for the development of off-the-shelf vaccines as they are often found in multiple types of cancer (4). Since TAAs are mainly involved in processes essential for the survival of cancer cells, they are less likely to have their expression downregulated, which increases their appeal as therapeutic strategies. However, despite their potential, TAAs are not uniquely expressed in tumor cells, a feature that makes them potentially less immunogenic and more likely to be associated with “off-target” effects (4).
After immunization, specialized immune cells called dendritic cells take up the selected antigens, process them, and expose these tumor-related molecules on their surfaces. These antigen-presenting cells then migrate to immune activation sites, such as lymph nodes, where they display the antigens to naïve T cells. These immune cells go on to proliferate and differentiate into antigen-specific T cells that can infiltrate the tumor microenvironment and kill cancerous cells directly and through cytokine-mediated processes. In parallel, some T cells can also help activate B cells, which produce antibodies that flag cancer cells for destruction by immune cells (4). Collectively, these cellular, antibody, and cytokine-mediated responses contribute to anti-tumor immunity.
From the past into the future: Advances in therapeutic cancer vaccines
While the first clinical trials using TAAs date back to the early 1990s, FDA’s first therapeutic cancer vaccine approval took another 20 years (2010), when the agency authorized a vaccine (Sipuleucel-T) for the treatment of hormone-refractory prostate cancer (5). Since then, the field of therapeutic cancer vaccine development has seen significant progress, with several fresh approaches for antigen screening, new platforms, and delivery methods becoming available.
The development of computational methods and the use of high-throughput sequencing data have significantly advanced the identification of potential vaccine antigens, particularly neoantigens used in personalized treatments (6). With high-throughput sequencing technologies, such as whole-genome sequencing and whole-exome sequencing, scientists can now screen thousands of candidate antigens and test only the most promising ones for specific cancer vaccine applications. Computational models, in turn, offer a powerful tool for simulating and predicting the response to cancer vaccines or even improving the identification of neoantigens. For instance, by applying deep learning technologies in patient datasets, researchers are creating computational models that can help with neoantigen prediction (7).
In terms of new platforms, vaccines based on messenger RNA (mRNA) technologies are among the most promising. These vaccines have clear advantages as therapeutics, including their ability to be easily modified, their high immunogenicity, and their rapid manufacturing compared to peptide-based vaccines. They also pose no risk of genome integration, which is a concern associated with DNA-based vaccines (6).
While early clinical trials in 2017 showed the potential of personalized RNA-based vaccines for cancer treatment (8,9), a recent phase I clinical trial revealed their ability to induce long-lasting immunity against a form of pancreatic cancer, with immunity lasting nearly 4 years after treatment (10).
Several new delivery methods aimed at enhancing the precision of therapeutic cancer vaccines and improving the uptake of neoantigens by dendritic cells are also in development.
Outer membrane vesicles (OMVs) are one of such delivery systems (11). Naturally produced by Gram-negative bacteria, OMVs have unique properties that make them promising candidates for cancer vaccine development. First, they can be bioengineered to display selected tumor antigens on their surfaces. This, along with their nanometer size, could improve antigen presentation and uptake by dendritic cells. Additionally, OMVs have inherent adjuvant properties because they are covered with pathogen-associated molecular patterns (PAMPs), which are highly conserved molecules easily recognized by immune cells (11).
Although the development of OMV-based cancer vaccines is still in its infancy, recent studies have shown their potential as a therapeutic strategy for combating tumors in animal models (12,13).
In the context of mRNA-based vaccines, lipid nanoparticles (LNPs) are a promising delivery system. These nanoscopic particles can encapsulate mRNA molecules, enhancing their cellular uptake and stability by shielding them from degradation by nucleases (14).
Clinical studies of LNP-based mRNA vaccines are revealing their safety profiles and ability to induce specific immune responses, especially when combined with adjuvant therapies (14). These encouraging results have prompted some of these treatments to progress to phase II or III clinical trials.
As clinical trials advance, we will certainly get a clear picture of the benefits that therapeutic cancer vaccines can offer as immunotherapies. For now, it is safe to say that the advances discussed in this article and many others in the field reveal an optimistic path forward.
Header Image Source: Image created by the author using Canva. Source of background image: Tara Winstead, Pexels
Edited by Mikayla Sheild
References
1. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/antigen. http://www.cancer.gov. Published February 2, 2011. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/antigen
2. Cancer Vaccines: Educating Your Immune System Since the 1800s. OncoBites. Published May 16, 2018. Accessed June 24, 2025. https://oncobites.blog/2018/05/16/cancer-vaccines-educating-your-immune-system-since-the-1800s/#more-173
3. Feola S, Chiaro J, Martins B, Cerullo V. Uncovering the Tumor Antigen Landscape: What to Know about the Discovery Process. Cancers (Basel). 2020;12(6):1660. Published 2020 Jun 23. doi:10.3390/cancers12061660
4. Zaidi N, Jaffee EM, Yarchoan M. Recent advances in therapeutic cancer vaccines. Nat Rev Cancer. Published online May 16, 2025. doi:10.1038/s41568-025-00820-z
5. Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res. 2011;17(11):3520-3526. doi:10.1158/1078-0432.CCR-10-3126
6. Fan, T., Zhang, M., Yang, J., Zhu, Z., Cao, W., & Dong, C. (2023). Therapeutic cancer vaccines: advancements, challenges, and prospects. Signal transduction and targeted therapy, 8(1), 450. https://doi.org/10.1038/s41392-023-01674-3
7. Bulik-Sullivan B, Busby J, Palmer CD, et al. Deep learning using tumor HLA peptide mass spectrometry datasets improves neoantigen identification. Nat Biotechnol. Published online December 17, 2018. doi:10.1038/nbt.4313
8. Sahin U, Derhovanessian E, Miller M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017;547(7662):222-226. doi:10.1038/nature23003
9. Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients with melanoma [published correction appears in Nature. 2018 Mar 14;555(7696):402. doi: 10.1038/nature25145.]. Nature. 2017;547(7662):217-221. doi:10.1038/nature22991
10. Sethna Z, Guasp P, Reiche C, et al. RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer. Nature. 2025;639(8056):1042-1051. doi:10.1038/s41586-024-08508-4
11. Zhang Y, Fang Z, Li R, Huang X, Liu Q. Design of Outer Membrane Vesicles as Cancer Vaccines: A New Toolkit for Cancer Therapy. Cancers (Basel). 2019;11(9):1314. Published 2019 Sep 6. doi:10.3390/cancers11091314
12. Kim OY, Park HT, Dinh NTH, et al. Bacterial outer membrane vesicles suppress tumor by interferon-γ-mediated antitumor response. Nat Commun. 2017;8(1):626. Published 2017 Sep 20. doi:10.1038/s41467-017-00729-8
13. Cheng K, Zhao R, Li Y, et al. Bioengineered bacteria-derived outer membrane vesicles as a versatile antigen display platform for tumor vaccination via Plug-and-Display technology. Nat Commun. 2021;12(1):2041. Published 2021 Apr 6. doi:10.1038/s41467-021-22308-8
14. Jacob EM, Huang J, Chen M. Lipid nanoparticle-based mRNA vaccines: a new frontier in precision oncology. Precis Clin Med. 2024;7(3):pbae017. Published 2024 Aug 1. doi:10.1093/pcmedi/pbae017
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