The logic of therapeutic vaccination differs fundamentally from preventive immunization. Rather than blocking infection, these vaccines are designed to treat existing cancers by activating tumor-specific immunity and strengthening immune surveillance. Yet the review is candid about the field’s central frustration: even though endogenous T-cell responses against tumors exist in most patients, they typically fail to control disease, and immune checkpoint blockade (ICB) therapy—drugs that release the molecular brakes on T cells—often cannot rescue those responses on its own. Vaccines are meant to supply what the tumor microenvironment suppresses: a large, specific, and activated pool of anti-tumor T cells. Combining vaccines with checkpoint inhibitors has produced encouraging outcomes, including improved survival and tumor reduction across multiple cancer types, but low immunogenicity and tumor heterogeneity remain stubborn obstacles.

Nucleic acid vaccines are the fastest-moving segment of the field. DNA vaccines deliver bacterial plasmids encoding tumor-associated antigens (TAAs) or neoantigens into the cell nucleus, where they are transcribed into mRNA and translated into target proteins. They are stable, cheap to manufacture, easy to store, and can encode multiple antigens to hedge against tumor heterogeneity. The trade-offs are significant: DNA must cross the nuclear envelope, an extra step that lowers antigen production efficiency, and theoretical genomic integration remains a safety consideration unique to DNA. Because their intrinsic immunogenicity is low, DNA vaccines generally require adjuvants, electroporation, or nanoparticle delivery, and few clinical successes have been reported. One notable exception is GNOS-PV02, a DNA plasmid encoding up to 40 personalized neoantigens, which is being tested with an IL-12-encoding plasmid and the PD-1 antibody pembrolizumab in a phase 1/2 trial in hepatocellular carcinoma with promising early results.

mRNA vaccines have captured most of the attention, and the review argues the hype is at least partly earned. mRNA only needs to reach the cytoplasm to begin producing antigen, avoiding the nuclear barrier, and it cannot integrate into the genome. Advances in lipid nanoparticle (LNP) delivery have dramatically improved mRNA stability and cellular uptake, while self-amplifying mRNA (samRNA) promises prolonged antigen expression at lower doses, though cancer applications remain at an early preclinical and clinical stage. A double-edged sword is innate immune sensing: mRNA triggers pattern recognition receptors such as RIG-I and Toll-like receptors, which can act as a built-in adjuvant but can also induce type-I interferon responses that inhibit translation of the vaccine itself. The flagship candidate is mRNA-4157, which encodes up to 35 neoantigen epitopes and is delivered in LNPs. Combined with pembrolizumab, it improved recurrence-free survival versus pembrolizumab alone in a phase 2 trial of patients with completely resected, high-risk cutaneous melanoma, and phase 3 trials are now underway in melanoma, non-small cell lung cancer, and cutaneous squamous cell carcinoma.

Peptide vaccines take a more direct approach, administering synthetic polypeptides that mimic TAAs or neoantigens, which are captured by antigen-presenting cells and used to prime CD8-positive and CD4-positive T cells. Their Achilles’ heel is size: short peptides can load directly onto MHC molecules on any cell, including non-professional antigen-presenting cells that induce tolerance rather than immunity. Synthetic long peptides containing both MHC class I and class II epitopes avoid this trap and reliably induce both T-cell compartments. To overcome weak immunogenicity, researchers pair peptides with Toll-like receptor agonists, checkpoint inhibitors, or nanoparticle carriers such as virus-like particles and liposomes. Clinical results are accumulating: EVX-01, a personalized vaccine of up to 15 neoantigen epitopes with the CAF09b adjuvant, is in phase 1/2 testing alongside checkpoint inhibitors, and SurVaxM, targeting survivin in newly diagnosed glioblastoma, significantly prolonged patient survival in a phase 2 trial combined with pembrolizumab. A new phase 1 trial is evaluating a nine-peptide vaccine with the TLR1/2 ligand XS15 in acute myeloid leukemia patients in first remission.

Cell-based vaccines exploit whole cells rather than defined antigens. Dendritic cell (DC) vaccines harvest a patient’s own antigen-presenting cells, load them ex vivo with tumor lysates, peptides, or antigen-encoding RNA, and reinfuse them to activate cytotoxic T cells. Whole tumor cell vaccines, using irradiated or genetically modified tumor cells, present a broad antigen repertoire that hedges against heterogeneity, and are often supercharged with adjuvants such as GM-CSF. The category’s proof of principle is Provenge (sipuleucel-T), the FDA-approved autologous DC vaccine for prostate cancer. GVAX, an irradiated GM-CSF-secreting tumor cell vaccine, improved disease-free and overall survival in pancreatic cancer patients when combined with the antibodies urelumab and nivolumab in a phase 2 trial. Ongoing phase 2 studies are testing the neoantigen-loaded DC vaccine NeoDC-Vac after chemoradiotherapy in locally advanced esophageal squamous cell carcinoma, and an autologous tumor lysate-loaded cDC1 vaccine in ovarian cancer. The review notes that high production costs, labor-intensive manufacturing, and variable patient responses still constrain this platform.

Virus-based strategies come in two flavors. Oncolytic viruses preferentially infect and replicate inside tumor cells, exploiting abnormal surface receptor expression and the weakened antiviral signaling—blunted interferon and PKR pathways—characteristic of cancer. As infected cells lyse, they release reactive oxygen species, cytokines, and damage-associated molecular patterns that ignite both innate and adaptive immunity, and epitope spreading helps the immune system recognize tumor antigens beyond those the virus carries. The landmark agent is T-VEC, the first FDA-approved oncolytic therapy: an attenuated herpes simplex virus deleted for ICP34.5 to enhance tumor-selective replication and reduce neurovirulence, and engineered to carry the GM-CSF gene to recruit dendritic cells and macrophages into the tumor. Viral vector vaccines, by contrast, use engineered adenoviruses, lentiviruses, or vaccinia viruses to deliver antigen genes into host cells, mimicking natural infection so effectively that adjuvants are often unnecessary. Their vulnerability is pre-existing vector immunity, which can neutralize the vaccine—a problem managed by heterologous prime-boost strategies that switch vectors between doses.

Two technological currents are reshaping the entire field. The first is artificial intelligence: machine learning tools such as NetMHC and DeepHLA mine genomic and transcriptomic data to predict which tumor mutations will yield immunogenic neoantigens that bind a patient’s HLA molecules, bypassing central immune tolerance and reducing off-target risk. GNOS-PV02 already uses such algorithms to select neoantigens by predicted binding affinity. But the review cautions that limited training datasets and ethnic bias in HLA haplotype data can undermine the generalizability of predictions. The second is delivery engineering: LNP surface charge can be tuned to redirect biodistribution to different organs, cholesterol analogues such as C-24 alkyl phytosterols enhance in vivo mRNA delivery, hydrogels act as depots for sustained antigen release—with one study finding that D- versus L-glutamate chirality in polypeptide hydrogels profoundly altered immune cell infiltration and T-cell exhaustion—and lentiviral particles pseudotyped with Sindbis virus glycoprotein can target mRNA directly to dendritic cells, boosting both humoral and T-cell responses.

The review’s most sobering conclusion is that no vaccine platform, however elegant, is likely to deliver durable clinical benefit alone. Combination is the operative word: pairing vaccines with anti-PD-1 and anti-CTLA-4 antibodies, cytokines such as IL-2 and IL-15 superagonist ALT-803, adoptive cell transfers like tumor-infiltrating lymphocyte therapy, or even radiotherapy and chemotherapy that can convert immunologically cold tumors into inflamed ones by breaking down physical barriers of tumor-associated fibroblasts and poor vascularization. Underlying biology still constrains outcomes: HLA diversity between patients complicates neoantigen prediction and blocks some patients from accessing promising TAA epitopes, while individual T-cell receptor repertoires and pMHC densities produce highly variable T-cell avidity—and recent work suggests low-avidity T cells actually drive endogenous tumor immunity. Toxicity, patient variability, and treatment resistance complicate combination regimens. Still, with 15,000 accesses and growing citations since its May 2025 publication, the review captures a field at an inflection point: after decades of disappointment, therapeutic cancer vaccines—personalized, AI-designed, and rationally combined—are finally delivering on their immunological promise.

Subject of Research: Therapeutic cancer vaccine platforms and their combination with immunotherapy

Article Title: Therapeutic vaccine strategies in cancer: advances, challenges, and future directions

Article References: Therapeutic vaccine strategies in cancer: advances, challenges, and future directions. (n.d.). https://doi.org/10.1007/s44272-025-00039-x

Image Credits: AI Generated

DOI: 10.1007/s44272-025-00039-x

Keywords: therapeutic cancer vaccines, cancer immunotherapy, mRNA vaccines, DNA vaccines, neoantigens, peptide vaccines, dendritic cell vaccines, oncolytic viruses, viral vectors, immune checkpoint inhibitors, lipid nanoparticles, artificial intelligence