Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Google Scholar
Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).
Google Scholar
Swanton, C. Intratumor heterogeneity: evolution through space and time. Cancer Res 72, 4875–4882 (2012).
Google Scholar
Collins, F. S. & Varmus, H. A new initiative on precision medicine. N Engl. J Med. 372, 793–795 (2015).
Google Scholar
Mani, S., Lalani, S. R. & Pammi, M. Genomics and multiomics in the age of precision medicine. Pediatr. Res. 97, 1399–1410 (2025).
Google Scholar
Martinez-Perez, E., Molina-Vila, M. A. & Marino-Buslje, C. Panels and models for accurate prediction of tumor mutation burden in tumor samples. npj Precis. Oncol. 5, 31 (2021).
Google Scholar
Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol 20, 651–668 (2020).
Google Scholar
Melief, C. J. M. Cancer: precision T-cell therapy targets tumours. Nature 547, 165–167 (2017).
Google Scholar
Hu, Z. et al. Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma. Nat. Med. 27, 515–525 (2021).
Google Scholar
Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).
Google Scholar
Sahin, U. & Tureci, O. Personalized vaccines for cancer immunotherapy. Science 359, 1355–1360 (2018).
Google Scholar
Xie, N. et al. Neoantigens: promising targets for cancer therapy. Signal Transduct. Target Ther. 8, 9 (2023).
Google Scholar
Shariati, A. et al. mRNA cancer vaccines from bench to bedside: a new era in cancer immunotherapy. Biomark Res. 12, 157 (2024).
Google Scholar
Joyce, S. In Handbook of Cancer and Immunology (Ed: N. Rezaei), Springer, Cham. 1–40, https://doi.org/10.1007/978-3-030-80962-1_38-1 (2023).
Hao, Q. et al. Development and clinical applications of therapeutic cancer vaccines with individualized and shared neoantigens. Vaccines https://doi.org/10.3390/vaccines12070717 (2024).
Zhang, J. Y., Looi, K. S. & Tan, E. M. Identification of tumor-associated antigens as diagnostic and predictive biomarkers in cancer. Methods Mol. Biol. 520, 1–10 (2009).
Google Scholar
Bright, R. K., Bright, J. D. & Byrne, J. A. Overexpressed oncogenic tumor-self antigens. Hum. Vaccin. Immunother 10, 3297–3305 (2014).
Google Scholar
Feola, S., Chiaro, J., Martins, B. & Cerullo, V. Uncovering the tumor antigen landscape: what to know about the discovery process. Cancers https://doi.org/10.3390/cancers12061660 (2020).
Dolton, G. et al. Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy. Cell 186, 3333–3349.e27 (2023).
Google Scholar
Arroyo Muhr, L. S. et al. Concomitant human papillomavirus (HPV) vaccination and screening for elimination of HPV and cervical cancer. Nat. Commun. 15, 3679 (2024).
Google Scholar
Huang, M. et al. Hepatitis B virus promotes liver cancer by modulating the immune response to environmental carcinogens. Nat. Commun. 16, 5360 (2025).
Google Scholar
Zhang, H. et al. Oncogenic viral antigens for engineered T cell immunotherapy: challenges and opportunities. Med. Adv. 1, 306–317 (2023).
Google Scholar
Li, X. et al. Neoantigen cancer vaccines: a new star on the horizon. Cancer Biol. Med. 21, 274–311 (2023).
Google Scholar
De Plaen, E. et al. Immunogenic (tum-) variants of mouse tumor P815: cloning of the gene of tum-antigen P91A and identification of the tum-mutation. Proc. Natl. Acad. Sci. USA 85, 2274–2278 (1988).
Google Scholar
Keskus, A. G. et al. Severus detects somatic structural variation and complex rearrangements in cancer genomes using long-read sequencing. Nat. Biotechnol. 44, 247–257 (2026).
Google Scholar
Ghoreyshi, N. et al. Next-generation sequencing in cancer diagnosis and treatment: clinical applications and future directions. Discov. Oncol. 16, 578 (2025).
Google Scholar
Lang, F., Schrors, B., Lower, M., Tureci, O. & Sahin, U. Identification of neoantigens for individualized therapeutic cancer vaccines. Nat. Rev. Drug Discov. 21, 261–282 (2022).
Google Scholar
Wells, D. K. et al. Key parameters of tumor epitope immunogenicity revealed through a consortium approach improve neoantigen prediction. Cell 183, 818–834.e13 (2020).
Google Scholar
Fan, T. et al. Therapeutic cancer vaccines: advancements, challenges, and prospects. Signal Transduct. Target Ther. 8, 450 (2023).
Google Scholar
Li, T. et al. Artificial intelligence in cancer immunotherapy: applications in neoantigen recognition, antibody design and immunotherapy response prediction. Semin. Cancer Biol. 91, 50–69 (2023).
Google Scholar
Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N Engl. J Med. 377, 2500–2501 (2017).
Google Scholar
Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 30, 44–56 (2019).
Google Scholar
Guo, Y., Lei, K. & Tang, L. Neoantigen vaccine delivery for personalized anticancer immunotherapy. Front Immunol. 9, 1499 (2018).
Google Scholar
Stephens, A. J., Burgess-Brown, N. A. & Jiang, S. Beyond just peptide antigens: the complex world of peptide-based cancer vaccines. Front Immunol. 12, 696791 (2021).
Google Scholar
Wang, L. et al. Therapeutic peptides: current applications and future directions. Signal Transduct. Target Ther. 7, 48 (2022).
Google Scholar
Reynisson, B. et al. Improved prediction of MHC II antigen presentation through integration and motif deconvolution of mass spectrometry MHC eluted ligand data. J Proteome Res. 19, 2304–2315 (2020).
Google Scholar
Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).
Google Scholar
Kutzler, M. A. & Weiner, D. B. DNA vaccines: ready for prime time? Nat. Rev. Genet 9, 776–788 (2008).
Google Scholar
Lopes, A., Vandermeulen, G. & Preat, V. Cancer DNA vaccines: current preclinical and clinical developments and future perspectives. J Exp. Clin Cancer Res. 38, 146 (2019).
Google Scholar
Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).
Google Scholar
Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021).
Google Scholar
Kon, E., Elia, U. & Peer, D. Principles for designing an optimal mRNA lipid nanoparticle vaccine. Curr. Opin Biotechnol. 73, 329–336 (2022).
Google Scholar
Dilliard, S. A. & Siegwart, D. J. Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs. Nat. Rev. Mater. 8, 282–300 (2023).
Google Scholar
Miao, L., Zhang, Y. & Huang, L. mRNA vaccine for cancer immunotherapy. Mol. Cancer 20, 41 (2021).
Google Scholar
Verbeke, R., Hogan, M. J., Lore, K. & Pardi, N. Innate immune mechanisms of mRNA vaccines. Immunity 55, 1993–2005 (2022).
Google Scholar
Wang, B., Pei, J., Xu, S., Liu, J. & Yu, J. Recent advances in mRNA cancer vaccines: meeting challenges and embracing opportunities. Front Immunol 14, 1246682 (2023).
Google Scholar
Fu, Q. et al. mRNA vaccines in the context of cancer treatment: from concept to application. J Transl. Med. 23, 12 (2025).
Google Scholar
Dobrowolski, C., Paunovska, K., Hatit, M. Z. C., Lokugamage, M. P. & Dahlman, J. E. Therapeutic RNA delivery for COVID and other diseases. Adv. Healthc Mater. 10, e2002022 (2021).
Google Scholar
Lopes de Abreu, A. d. J. et al. Unpacking the mRNA supply chain: challenges and opportunities for global health. Vaccines https://doi.org/10.3390/vaccines14040324 (2026).
Ibragimova, A. A. et al. mRNA-based personalized cancer vaccines: opportunities, challenges and outcomes. Acta Naturae 17, 17–37 (2025).
Google Scholar
Garg, P., Salgia, R. & Singhal, S. S. mRNA-based cancer vaccines: a new frontier in personalized immunotherapy. Biochim. Biophys. Acta Rev. Cancer 1881, 189577 (2026).
Google Scholar
Xie, C., Yao, R. & Xia, X. The advances of adjuvants in mRNA vaccines. npj Vaccines 8, 162 (2023).
Google Scholar
Giles, J. R., Globig, A. M., Kaech, S. M. & Wherry, E. J. CD8+ T cells in the cancer-immunity cycle. Immunity 56, 2231–2253 (2023).
Google Scholar
Philip, M. & Schietinger, A. CD8+ T cell differentiation and dysfunction in cancer. Nat. Rev. Immunol. 22, 209–223 (2022).
Google Scholar
Raskov, H., Orhan, A., Christensen, J. P. & Gogenur, I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer 124, 359–367 (2021).
Google Scholar
Hinks, T. S. C., Hoyle, R. D. & Gelfand, E. W. CD8+ Tc2 cells: underappreciated contributors to severe asthma. Eur. Respir. Rev. https://doi.org/10.1183/16000617.0092-2019 (2019).
Koh, C. H., Lee, S., Kwak, M., Kim, B. S. & Chung, Y. CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential. Exp. Mol. Med. 55, 2287–2299 (2023).
Google Scholar
Mishra, S., Srinivasan, S., Ma, C. & Zhang, N. CD8+ regulatory T cell — a mystery to be revealed. Front Immunol. 12, 708874 (2021).
Google Scholar
Su, X. et al. Mechanisms of T-cell depletion in tumors and advances in clinical research. Biol. Proced Online 27, 5 (2025).
Google Scholar
Bawden, E. & Gebhardt, T. The multifaceted roles of CD4+ T cells and MHC class II in cancer surveillance. Curr. Opin Immunol. 83, 102345 (2023).
Google Scholar
Crater, J. M., Dunn, D. C., Nixon, D. F. & Furler O’Brien, R. L. A history and atlas of the human CD4+ T helper cell. Biomedicines https://doi.org/10.3390/biomedicines11102608 (2023).
Pu, J. et al. T cells in cancer: mechanistic insights and therapeutic advances. Biomark Res. 13, 97 (2025).
Google Scholar
Tay, R. E., Richardson, E. K. & Toh, H. C. Revisiting the role of CD4+ T cells in cancer immunotherapy — new insights into old paradigms. Cancer Gene. Ther. 28, 5–17 (2021).
Google Scholar
Topchyan, P., Lin, S. & Cui, W. The role of CD4 T cell help in CD8 T cell differentiation and function during chronic infection and cancer. Immune Netw. 23, e41 (2023).
Google Scholar
Cenerenti, M., Saillard, M., Romero, P. & Jandus, C. The era of cytotoxic CD4 T cells. Front Immunol 13, 867189 (2022).
Google Scholar
Macy, A. M., Herrmann, L. M., Adams, A. C. & Hastings, K. T. Major histocompatibility complex class II in the tumor microenvironment: functions of nonprofessional antigen-presenting cells. Curr. Opin. Immunol. 83, 102330 (2023).
Google Scholar
Quezada, S. A. et al. Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp. Med. 207, 637–650 (2010).
Google Scholar
Fritah, H., Rovelli, R., Chiang, C. L. & Kandalaft, L. E. The current clinical landscape of personalized cancer vaccines. Cancer Treat Rev. 106, 102383 (2022).
Google Scholar
Weber, J. S. et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 403, 632–644 (2024).
Google Scholar
Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023).
Google Scholar
Sethna, Z. et al. RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer. Nature 639, 1042–1051 (2025).
Google Scholar
Jeng, L. B., Liao, L. Y., Shih, F. Y. & Teng, C. F. Dendritic-cell-vaccine-based immunotherapy for hepatocellular carcinoma: clinical trials and recent preclinical studies. Cancers https://doi.org/10.3390/cancers14184380 (2022).
Sheykhhasan, M. et al. Revolutionizing cancer treatment: the power of dendritic cell-based vaccines in immunotherapy. Biomed. Pharmacother 184, 117858 (2025).
Google Scholar
Cheever, M. A. & Higano, C. S. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res. 17, 3520–3526 (2011).
Google Scholar
Jaroslawski, S. & Toumi, M. Sipuleucel-T (Provenge((R))) — autopsy of an innovative paradigm change in cancer treatment: why a single-product Biotech Company failed to capitalize on its breakthrough invention. BioDrugs 29, 301–307 (2015).
Google Scholar
Borch, T. H. et al. mRNA-transfected dendritic cell vaccine in combination with metronomic cyclophosphamide as treatment for patients with advanced malignant melanoma. Oncoimmunology 5, e1207842 (2016).
Google Scholar
Do, A. S. S. et al. CD133 mRNA-loaded dendritic cell vaccination abrogates glioma stem cell propagation in humanized glioblastoma mouse model. Mol. Ther. Oncol. 18, 295–303 (2020).
Google Scholar
Berraondo, P. et al. Cytokines in clinical cancer immunotherapy. Br J Cancer 120, 6–15 (2019).
Google Scholar
Kong, B., Kim, Y., Kim, E. H., Suk, J. S. & Yang, Y. mRNA: a promising platform for cancer immunotherapy. Adv. Drug Deliv. Rev. 199, 114993 (2023).
Google Scholar
Wu, X. et al. Targeting MHC-I molecules for cancer: function, mechanism, and therapeutic prospects. Mol. Cancer 22, 194 (2023).
Google Scholar
Cho, S. et al. Rapid-turnaround co-administration of mRNA-based MHC-I and MHC-II-restricted neoantigens enhances immune responses of antigen-specific CD8(+) T cells and anti-cancer efficacy in colorectal cancer. Adv. Sci. 12, e06426 (2025).
Google Scholar
Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).
Google Scholar
Huff, A. L. et al. CD4 T cell-activating neoantigens enhance personalized cancer vaccine efficacy. JCI Insight https://doi.org/10.1172/jci.insight.174027 (2023).
Zhang, Y. et al. Advances and challenges in neoantigen prediction for cancer immunotherapy. Front Immunol. 16, 1617654 (2025).
Google Scholar
Munz, C. Antigen processing for MHC class II presentation via autophagy. Front Immunol. 3, 9 (2012).
Google Scholar
Richters, M. M. et al. Best practices for bioinformatic characterization of neoantigens for clinical utility. Genome Med. 11, 56 (2019).
Google Scholar
Wang, Z., Gu, Y., Sun, X. & Huang, H. Computation strategies and clinical applications in neoantigen discovery towards precision cancer immunotherapy. Biomark Res. 13, 96 (2025).
Google Scholar
Ely, Z. A. et al. Pancreatic cancer-restricted cryptic antigens are targets for T cell recognition. Science 388, eadk3487 (2025).
Google Scholar
Becker, W. & Rathmell, W. K. Vaccines in cancer treatment and prevention: the time is now. J Clin Invest https://doi.org/10.1172/JCI195673 (2025).
Ruzzi, F. et al. Cancer vaccines: target antigens, vaccine platforms and preclinical models. Mol. Aspects Med. 101, 101324 (2025).
Google Scholar
Sankar, K. et al. The role of biomarkers in personalized immunotherapy. Biomark Res. 10, 32 (2022).
Google Scholar
Harrop, R. Cancer vaccines: identification of biomarkers predictive of clinical efficacy. Hum. Vaccin Immunother 9, 800–804 (2013).
Google Scholar
Verma, N. K. et al. Obstacles for T-lymphocytes in the tumour microenvironment: therapeutic challenges, advances and opportunities beyond immune checkpoint. eBioMedicine 83, 104216 (2022).
Google Scholar
Kim, C. G., Sang, Y. B., Lee, J. H. & Chon, H. J. Combining cancer vaccines with immunotherapy: establishing a new immunological approach. Int. J Mol. Sci. https://doi.org/10.3390/ijms22158035 (2021).
Rukhayya, F. et al. Personalized cancer vaccines in combination therapies: current status and future prospects. Asian Pac. J Cancer Prev. 26, 2741–2754 (2025).
Google Scholar
Zhou, Y., Wei, Y., Tian, X. & Wei, X. Cancer vaccines: current status and future directions. J Hematol Oncol. 18, 18 (2025).
Google Scholar
Lee, J. B., Kim, H. R. & Ha, S. J. Immune checkpoint inhibitors in 10 years: contribution of basic research and clinical application in cancer immunotherapy. Immune Netw. 22, e2 (2022).
Google Scholar
Capitini, C. M., Fry, T. J. & Mackall, C. L. Cytokines as adjuvants for vaccine and cellular therapies for cancer. Am J Immunol. 5, 65–83 (2009).
Google Scholar
Li, Z. et al. Local administration of mRNA encoding cytokine cocktail confers potent anti-tumor immunity. Front Immunol. 15, 1455019 (2024).
Google Scholar
The Lancet, O. Personalised cancer vaccines and new regulatory struggles. Lancet Oncol. 26, 265 (2025).
Google Scholar
Shemesh, C. S. et al. Personalized cancer vaccines: clinical landscape, challenges, and opportunities. Mol. Ther. 29, 555–570 (2021).
Google Scholar
U.S. Food and Drug Administration. Using Artificial Intelligence & Machine Learning in the Development of Drug & Biological Products: Discussion Paper and Request for Feedback. Federal Register, 88 FR 30313 (2023).
Vitiello, A. & Zanetti, M. Neoantigen prediction and the need for validation. Nat. Biotechnol. 35, 815–817 (2017).
Google Scholar
United States Pharmacopeia Convention. <71> Sterility Tests. Report No. USP-NF General Chapter <71> (United States Pharmacopeia, 2008).
EMA. EMA Guideline on Quality, Non-clinical and Clinical Requirements for Investigational Advanced Therapy Medicinal Products in Clinical Trials. Report No. EMA/CAT/22473/2025 (Committee for Advanced Therapies (CAT), EMA, 2025).
Progressing EMA’s PRIority Medicines Scheme Through New Pilot Features (European Medicines Agency, 2026). https://www.ema.europa.eu/en/documents/report/progressing-emas-priority-medicines-scheme-through-new-pilot-features_en.pdf.
Scheineson, M. J. et al. Regenerative Medicine, Gene Therapies, and FDA Regulation. In Proceedings of the 2019 FDLI Annual Conference. Food and Drug Law Institute (FDLI), Washington, DC, USA.
Ott, P. A. et al. A phase Ib trial of personalized neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. Cell 183, 347–362.e24 (2020).
Google Scholar
Yarchoan, M. et al. Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial. Nat. Med. 30, 1044–1053 (2024).
Google Scholar
Ding, Z. et al. Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer. Signal Transduct. Target Ther. 6, 26 (2021).
Google Scholar
Chen, Z. et al. A neoantigen-based peptide vaccine for patients with advanced pancreatic cancer refractory to standard treatment. Front Immunol. 12, 691605 (2021).
Google Scholar
Wu, A. A. et al. Personalizing DNA cancer vaccines. J Pers. Med. https://doi.org/10.3390/jpm15100474 (2025).
Ingels, J. et al. Neoantigen-targeted dendritic cell vaccination in lung cancer patients induces long-lived T cells exhibiting the full differentiation spectrum. Cell Rep. Med. 5, 101516 (2024).
Google Scholar
Bauman, J. E. et al. Abstract CT141: mRNA-4157 (V940) individualized neoantigen therapy (INT) + pembrolizumab (pembro) in advanced unresectable HPV- head & neck carcinoma (HNSCC): clinical & translational analysis. Cancer Res. 84, CT141 (2024).
Google Scholar
Awad, M. M. et al. Personalized neoantigen vaccine NEO-PV-01 with chemotherapy and anti-PD-1 as first-line treatment for non-squamous non-small cell lung cancer. Cancer Cell 40, 1010–1026.e11 (2022).
Google Scholar
