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At least 19 recordsLinked to original sources
PubMed2026

Artificial intelligence for translational personalized neoantigen cancer vaccine development.

Personalized neoantigen cancer vaccine is a promising strategy for precision immunotherapy by targeting patient-specific and mutation-derived tumor antigens. Early clinical studies have demonstrated the feasibility, safety, and immunogenicity of these vaccines across multiple solid tumors, with encouraging outcomes particularly when combined with immune checkpoint blockade. However, broader clinical translation remains limited by sequential bottlenecks across the vaccine development pipeline, including false-positive neoantigen selection,  imperfect modeling of antigen processing and HLA presentation, limited prediction of T-cell receptor recognition, and challenges in formulation, delivery, and manufacturing. Artificial intelligence and advanced computational workflows are increasingly integrated into this pipeline to improve candidate prioritization and support more reproducible decision-making. In this review, we summarize clinical progress and key translational barriers in personalized neoantigen vaccination, and discuss how AI-enabled approaches may contribute across four major stages: multi-omics integration for neoantigen discovery, processing-aware HLA presentation prediction, structure-aware and TCR-informed immunogenicity modeling, and data-driven formulation optimization, particularly for lipid nanoparticle-based delivery systems. These approaches are able to help narrow biological and chemical search spaces, improve prioritization, and provide mechanistic insights into antigen presentation and immune recognition rather than replacing experimental validation. This articlefurther addresses future implementation challenges, including dataset diversity, model interpretability, prospective benchmarking, manufacturing traceability, and evolving regulatory frameworks for individualized mRNA cancer immunotherapies. Integrating computational innovation with rigorous immunological validation, scalable manufacturing, and regulatory oversight will be essential for advancing personalized neoantigen vaccines toward broader clinical implementation.

Cancer Vaccines↗
PubMed2026

Synthetic long peptide and DNA personalized cancer vaccines induce robust neoantigen-specific T cell responses in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is unresponsive to standard immunotherapies despite harboring cancer neoantigens capable of eliciting T cell responses. We completed two phase 1 clinical trials (NCT03956056 and NCT03122106) evaluating safety and immunogenicity of synthetic long peptide (SLP) and DNA personalized cancer vaccines (PCVs). PCVs were administered after resection and adjuvant chemotherapy. Tumor/normal whole-exome sequencing, RNA sequencing, and pVACtools were used to identify and prioritize candidate PCV neoantigens. PCVs were well tolerated without any grade ≥3 adverse events. Neoantigen-specific responses were demonstrated by interferon-γ enzyme-linked immunospot and intracellular cytokine staining. Expanded T cell receptor clonotypes were sequenced and transduced into autologous peripheral blood mononuclear cells to confirm neoantigen specificity. When compared with a contemporaneous institutional propensity-matched cohort, PCV patients demonstrated a trend toward prolonged median overall survival (4.4 versus 3.5 years, log-rank P = 0.23). Overall, PDAC PCVs are safe and feasible and elicit polyclonal T cell responses, linking prioritized cancer neoantigens to functional antitumor immunity.

Humans↗
PubMed2026

Immunopeptidomics-guided cancer vaccine design: Advances, challenges, and emerging opportunities.

Selecting clinically relevant tumor antigens remains a major challenge in the development of therapeutic cancer vaccines. Although computational approaches have considerably improved neoantigen prediction, many candidate epitopes identified in silico are not ultimately presented on the tumor cell surface. The emergence of immunopeptidomics has provided direct access to naturally processed HLA-associated peptides and has offered new opportunities for antigen discovery. Increasing evidence has shown that information derived from the immunopeptidome becomes considerably more informative when interpreted alongside genomic, transcriptomic, and proteomic data. This integrative view has broadened the spectrum of targetable antigens and has also revealed important limitations related to peptide abundance, HLA diversity, tumor heterogeneity, and the imperfect relationship between antigen presentation and immunogenicity. These issues have renewed interest in multi-antigen vaccine strategies designed to better reflect the complexity of tumor antigen landscapes. Advances in bioinformatics and artificial intelligence are facilitating the interpretation of increasingly complex datasets and are beginning to support more systematic approaches to antigen prioritization. In this review, we discuss how immunopeptidomics is contributing to next-generation cancer vaccine development, summarize the major translational challenges, and highlight emerging concepts that may improve the clinical applicability of immunopeptidomics-guided immunotherapy.

Cancer immunotherapy↗
PubMed2026

Beyond Canonical Neoantigens: Emerging Technologies for Identification of Noncanonical Antigens and Implications for Personalized Cancer Vaccines.

Over the past decade, advances in sequencing technologies and computational pipelines enabled the development of personalized cancer vaccines (PCVs). Current PCV strategies primarily target cancer neoantigens generated by non-synonymous DNA mutations, which can result in altered amino acid sequences capable of eliciting tumor-specific immune responses. More recently, a distinct class of tumor-specific antigens (TSA), termed noncanonical or cryptic antigens, has emerged as an additional source of immunogenic targets. Unlike canonical neoantigens, noncanonical antigens typically cannot be identified by tumor/normal whole-exome sequencing, as they do not arise from classical DNA mutations. Instead, they are often associated with less well recognized and/or aberrant processes in the pathways from DNA to human leukocyte antigen (HLA)-presented peptides. Examples include transposable elements, circular RNA, translation of alternative open reading frames and/or long non-coding RNA, among others. Emerging evidence suggests that noncanonical antigens represent a substantial portion of the tumor-specific immunopeptidome and, similar to canonical neoantigens, are absent during thymic selection and can evade central tolerance and elicit T cell responses. Technological advances have increasingly facilitated the identification of noncanonical antigens. Long-read RNA sequencing reveals noncanonical transcripts by improving transcriptome assembly, while ribosome profiling provides genome-wide maps of actively translated regions, facilitating the discovery of peptides from aberrant translation events. Specialized molecular approaches enable enrichment and sequencing of circular RNAs, and immunopeptidomics using mass spectrometry allows for direct characterization of HLA-presented peptides. Together, these technological advances have led to an increasing interest in prioritizing and targeting noncanonical antigens in the next generation of PCVs. This review provides an overview of the diverse origins of TSAs beyond classical neoantigens and discusses emerging approaches that may enable the integration of these antigens in future clinical trials.

circular RNA↗
PubMed2025

Plant-derived recombinant macromolecular PAP-IgG Fc as a novel prostate cancer vaccine candidate eliciting robust immune responses.

Prostatic acid phosphatase (PAP) is a specific protein that is highly expressed in prostate cancer. In this study, we constructed two recombinant PAP fusion genes: PAP fused to the immunoglobulin G (IgG) Fc fragment (designated PAP-Fc) and PAP-Fc fused to the endoplasmic reticulum retention sequence KDEL (designated PAP-FcK). Transgenic Nicotiana tabacum plants expressing these recombinant macromolecular proteins (MPs) were generated using Agrobacterium-mediated transformation, and the presence of both genes was confirmed through genomic PCR. Western blot analysis validated the expression of PAP-Fc and PAP-FcK MPs, which were successfully purified via protein A affinity chromatography. Size-exclusion high-performance liquid chromatography revealed dimeric peaks for PAP-Fc (PAP-FcP) and PAP-FcK (PAP-FcKP). Bio-transmission electron microscopy demonstrated 'Y'-shaped protein particles resembling antibody structures. Moreover, PAP-FcP and PAP-FcKP exhibited a high association rate with human FcγR and FcRn. Vaccination of mice with both PAP-FcP and PAP-FcKP resulted in increased total IgG against PAP and enhanced activation of CD4+ T cells, comparable to mice immunized with PAP, which served as a positive control. These findings indicate that both plant-derived MPs can effectively induce adaptive immunity, positioning them as promising candidates for prostate cancer vaccines. Overall, plants expressing PAP-Fc and PAP-FcK represent a viable production system for antigenic macromolecule-based prostate cancer vaccines.

Male↗
PubMed2025

A Programmable Nanovaccine Platform Based on M13 Bacteriophage for Personalized Cancer Vaccine and Therapy.

Nanovaccines co-assemble antigens and adjuvants to elicit robust immune responses but often require complex synthesis and post-modification procedures. Here, a programmable nanovaccine platform based on the M13 bacteriophage is developed for the scalable production of vaccines and single-step modular engineering of adjuvanticity, length, and antigen density. By reprogramming the sequence and size of the noncoding phage genome, the Toll-like receptor 9 activation and the length of the phage are precisely controlled. With a novel molecular engineering approach, the antigen density is tuned from 13.6% to 70.3%. A systematic modulation reveals an optimal adjuvanticity at a constant antigen density for maximum anti-tumor CD8+ T cell response, and vice versa, using the model antigen SIINFEKL. The M13 phage-based nanovaccine induces durable memory immunity lasting over a year. In addition, a 24-fold increase in neoantigen-specific CD8+ T cell frequency is achieved when increasing both the adjuvanticity and antigen density. Furthermore, when combined with anti-PD-1 therapy, the M13 phage-based personalized vaccine eradicates established MC-38 tumors in 75% of treated animals and they develop 100% resistance against tumor invasion when challenged 5 months after treatment. These findings establish M13 phage as a powerful and versatile nanovaccine platform with transformative potential for personalized cancer immunotherapy.

Cancer Vaccines↗
PubMed1975

Immunotherapy and vaccination against cancer with non-living BCG and cord factor (trehalose-6,6'-dimycolate).

A vaccine containing non-living BCG and living tumour cells prevented the growth of 106 tumour cells introduced distally into the skin of guinea-pigs at the time of vaccination. A similar effect was achieved when living tumour cells of the vaccine were replaced by tumour cells pretreated with mitomycin C. The efficacy of the vaccine was significantly increased when cord factor was added to the vaccination mixture. The percentage of cures was about 88% (17 cases) in experiments in which the vaccine contained living tumour cells, 100% (10 cases) when mitomycin C-treated cells were used. The significance and implications of the above findings are discussed.

Animals↗
PubMed1978

Prospects of vaccines against cancer in man.

Preventive immunization is the cheapest and most effective approach to the management of epidemic disease. Certain forms of cancer, including Burkitt's lymphoma, carcinoma of the cervix, primary liver cancer, acute leukaemia and breast cancer show many characteristics of epidemic disease, and the possibility of producing preventive vaccine against these conditions merits serious consideration.

Animals↗
PubMed2026

PRMT5-mediated intron retention triggers innate and adaptive immunity against cancer.

PRMT5 is expressed at high levels in many cancers, where it regulates diverse cellular pathways that contribute to oncogenesis. Here, we have defined a new role for PRMT5 in regulating and coordinating the interplay between the innate and adaptive immune response. This occurs, in part, through the influence of PRMT5 and E2F1 on RNA splicing and the presence of retained introns (RIs). We found that RIs have a propensity to form double-stranded RNAs that contribute to the innate response. Furthermore, many RIs contain non-canonical open-reading frames (ncORFs), which can be translated and then processed into small peptides that assemble with the MHC class I complex. Significantly, RI-derived peptides are highly immunogenic and, as a murine cancer vaccine, carrying a string of antigenic RI peptides, delayed tumour growth and enhanced survival. RIs are present in human tumour cells, and we identified T lymphocytes in human cancer patients, with antigen specificity for RI-derived peptides, that killed human tumour cells in vitro. Regulating intron retention thus offers a new therapeutic approach to enhance tumour immunogenicity.

Animals↗
PubMed1976

Vaccination of nonhuman primates with killed oncogenic herpesviruses.

Killed herpesvirus cancer vaccines were prepared by inactivation of oncogenic herpesviruses (Herpesvirus saimiri and Herpesvirus ateles) with heat and formaldehyde. The killed vaccines, which are not free of viral nucleic acid, were safe in 121 vaccinated monkeys of 4 different species. Some of these monkeys have now been under observation for 2 years. The vaccines induced high titers of specific humoral antibodies in all vaccinated monkeys. The killed vaccines proved to be efficient against the i.m. challenge with cell-free oncogenic herpesviruses. The challenged animals remained clinically well without signs of an infection and have now been under observation for 1 year, while the nonvaccinated control monkeys died of malignant lymphoma 34 to 52 days after inoculation. The protection against H. saimiri could be passively transmitted with the serum of the vaccinated monkeys. The vaccination did not prevent but delayed tumor development after tumor cell transplantation. The resistance against the oropharyngeal route of infection remains to be determined.

Animals↗
PubMed2025

Characterization of Tumor Antigens from Multi-omics Data: Computational Approaches and Resources.

Tumor-specific antigens, also known as neoantigens, have potential utility in anti-cancer immunotherapy, including immune checkpoint blockade (ICB), neoantigen-specific T cell receptor-engineered T (TCR-T), chimeric antigen receptor T (CAR-T), and therapeutic cancer vaccines (TCVs). After recognizing presented neoantigens, the immune system becomes activated and triggers the death of tumor cells. Neoantigens may be derived from multiple origins, including somatic mutations (single nucleotide variants, insertions/deletions, and gene fusions), circular RNAs, alternative splicing, RNA editing, and polymorphic microbiomes. An increasing amount of bioinformatics tools and algorithms are being developed to predict tumor neoantigens derived from different sources, which may require inputs from different multi-omics data. In addition, calculating the peptide-major histocompatibility complex (MHC) affinity can aid in selecting putative neoantigens, as high binding affinities facilitate antigen presentation. Based on these approaches and previous experiments, many resources have been developed to reveal the landscape of tumor neoantigens across multiple cancer types. Herein, we summarize these tools, algorithms, and resources to provide an overview of computational analysis for neoantigen discovery and prioritization, as well as the future development of potential clinical utilities in this field.

Humans↗
PubMed2026

Cancer Immunotherapy: Therapeutic Limitations and Next-Generation Precision Strategies.

Cancer immunotherapy has reshaped oncology, largely through immune checkpoint inhibitors that release the brakes on tumor-reactive T cells. Yet the benefit remains uneven, and that unevenness traces back to a few basic biological limits. Checkpoint blockade amplifies immunity that is already present; it does not create tumor specificity de novo. Poor Ag quality, defective Ag presentation, a suppressive microenvironment, and epigenetically fixed T-cell exhaustion together set a ceiling on what checkpoint release can achieve. Next-generation strategies try to move past these limits by reorganizing immunotherapy around the functional layers of the immune response. Cancer vaccines define tumor-specific neoantigens and expand the responses against them. Ab-based approaches tune inhibitory signaling, draw immune cells toward the tumor, and trigger immunogenic cell death. Cellular therapies-chimeric Ag receptor T cell, TCR-engineered T cells, and tumor-infiltrating lymphocytes (TILs)-boost effector potency, with TIL therapy notable for preserving tumor-reactive repertoires shaped in vivo. Rather than rivals, these modalities are best seen as complementary layers-Ag definition, immune priming, effector optimization, and microenvironmental conditioning-to be combined in a programmable way. As genomic profiling, immunopeptidomics, and high-dimensional immune monitoring mature, the field is shifting from checkpoint-centered release toward precision immunoengineering, in which tumor-specific immunity is deliberately designed, aligned, and sustained.

Cancer vaccines↗
PubMed2024

An isoform-resolution transcriptomic atlas of colorectal cancer from long-read single-cell sequencing.

Colorectal cancer (CRC) ranks as the second leading cause of cancer deaths globally. In recent years, short-read single-cell RNA sequencing (scRNA-seq) has been instrumental in deciphering tumor heterogeneities. However, these studies only enable gene-level quantification but neglect alterations in transcript structures arising from alternative end processing or splicing. In this study, we integrated short- and long-read scRNA-seq of CRC samples to build an isoform-resolution CRC transcriptomic atlas. We identified 394 dysregulated transcript structures in tumor epithelial cells, including 299 resulting from various combinations of splicing events. Second, we characterized genes and isoforms associated with epithelial lineages and subpopulations exhibiting distinct prognoses. Among 31,935 isoforms with novel junctions, 330 were supported by The Cancer Genome Atlas RNA-seq and mass spectrometry data. Finally, we built an algorithm that integrated novel peptides derived from open reading frames of recurrent tumor-specific transcripts with mass spectrometry data and identified recurring neoepitopes that may aid the development of cancer vaccines.

Colorectal Neoplasms↗
PubMed2026

Splenic hilum nodal involvement in resected left-sided pancreatic cancer: meta-analysis.

BACKGROUND: Splenectomy is standard of care during left pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) to obtain adequate lymphadenectomy. However, evidence supporting this approach is lacking. Splenic preservation would reduce short-term morbidity and is essential for emerging oncological adjunctive therapies, including immunotherapy and personalized cancer vaccines. This study reviewed the incidence of splenic hilum nodal involvement (SHNI) in left-sided PDAC. METHODS: A systematic review of the PubMed, Embase, and Cochrane databases was performed, identifying studies published from inception to July 2026. Outcomes of interest were the rate of SHNI (station 10), overall survival, and the rate of splenic artery nodal involvement (SANI; station 11). Meta-analyses were conducted using random-effects models. Subgroup analyses for SHNI were performed per tumour localization (pancreatic neck, body, tail). RESULTS: Among 2776 screened studies, 22 with 2260 patients undergoing left pancreatectomy for PDAC were included. The pooled prevalence of SHNI was 3.7% (95% confidence interval (c.i.) 2.2% to 6.2%); 1.1% for pancreatic body PDAC (95% c.i. 0.3% to 4.3%) and 9.7% for pancreatic tail PDAC (95% c.i. 3.5% to 24.0%). SHNI was not significantly associated with survival (pooled hazard ratio 2.05; 95% c.i. 0.89% to 4.72; P = 0.072). The pooled prevalence of SANI was 39.1% (95% c.i. 25.1% to 55.1%). CONCLUSION: In patients undergoing left pancreatectomy for PDAC, the presence of SHNI is rare, particularly in pancreatic body cancer (1.1%). These findings suggest that the relevance of routine splenectomy remains unclear, especially for pancreatic body PDAC. However, because the quality of current evidence is low, further investigation in prospective studies is required.

Humans↗
PubMed2026

EPIC: multi-objective guided diffusion for epitope design in TCR-pMHC complexes.

MOTIVATION: T cell receptor (TCR) recognition of peptide-major histocompatibility complex (pMHC) complexes is central to adaptive immunity, yet rational design of immunogenic epitopes remains elusive due to complex triplet binding constraints and data scarcity. No existing method can generate epitopes satisfying simultaneous requirements for antigenicity, MHC presentation, and TCR specificity. RESULTS: We present EPIC, a multi-objective diffusion framework that decomposes TCR-pMHC binding into three biologically grounded sub-tasks, enabling training-free gradient guidance without end-to-end retraining. By integrating ESM-based classifiers with a peptide diffusion generator, EPIC leverages heterogeneous immunological interaction datasets to generate diverse, context-aware epitopes. EPIC-designed top-three epitopes achieve lower predicted interface energies compared to ground-truth epitopes in 78.31% of test cases, while maintaining 80.1% sequence novelty and comparable structural confidence. Generated epitopes exhibit 100% uniqueness, high diversity (64.05%), and high antigenicity scores (0.4723). To our knowledge, EPIC is the first computational framework capable of de novo epitope design while explicitly integrating the triplet constraints of TCR-pMHC binding. This paradigm shift from discovery to design unlocks new potential for personalized cancer vaccines, precision adoptive T cell therapy, and rapid response to emerging infectious diseases. AVAILABILITY AND IMPLEMENTATION: The source code of EPIC is available at https://github.com/Octopus125/EPIC and archived on Zenodo (DOI: 10.5281/zenodo.18537646).

Receptors, Antigen, T-Cell↗
PubMed2026

Long-read sequencing reveals widespread novel splicing and neojunction-derived neoantigens in nasopharyngeal carcinoma.

The widespread transcriptomic diversity driven by alternative splicing (AS) contributes to all hallmarks of cancer and represents a critical source of neoantigens for personalized immunotherapy. However, unlike other major malignancies, the full repertoire of AS in nasopharyngeal carcinoma (NPC) remains underexplored. Here, we employ long-read sequencing (LR-seq) to generate a high-resolution, isoform-level transcriptomic atlas from a cohort of 14 NPC tumor samples and four immortalized nasopharyngeal epithelial cell lines. We identify a substantial number of full-length novel transcripts (22,687; ∼44.38%), which reveal diverse splicing patterns and previously unannotated splicing events. By integrating short-read RNA-seq data to quantify isoform expression, we discover a subset of novel transcripts that are differentially expressed between tumor samples and immortalized nasopharyngeal epithelial cell lines. Furthermore, LR-seq enables precise identification of chimeric readthrough fusion transcripts, such as CLDN15-FIS1 and FOXRED2-TXN2 Finally, we develop a computational framework, tumor-specific splicing neoantigen detection (TS-SNAD), to predict neoantigens originating from novel exon-exon junctions (neojunctions) in tumor-specific novel transcripts. Using this framework, we identify neojunction-derived neoantigens and experimentally validate the immunogenicity of selected HLA-B*40:01-restricted neoantigens. These neojunction-derived peptides constitute a new class of noncanonical neoantigens with significant potential for developing personalized cancer vaccines for NPC.

Humans↗
PubMed1978

Efficacy of BCG vaccination in prevention of cancer: an update.

From 1949 to 1951, a controlled trial of BCG vaccinations was conducted in Puerto Rico. The 191,827 children, 1-18 years of age, initially enrolled in the study were skin-tested with tuberculin to determine their eligibility for vaccination. A total of 82,269 children were classified as reactors and not vaccinated. Of the 109, 558 nonreactors, 31,586 refused vaccination, 50,634 were vaccinated with BCG, and 27,338 were left unvaccinated as controls. We ascertained the incidence of cancer over an average follow-up period of 23.3 years in the latter two groups using the Puerto Rico Central Cancer Registry. By the end of December 1973, a total of 77 cancers had been diagnosed among the controls and 150 among the vaccinees. The overall incidence of cancer among the two groups was similar. Although a number of differences existed between the vaccinee group and the controls in regard to the incidence of cancer at various "sites", none of these differences was statistically significant. However, when cases of lymphosarcoma and Hodgkin's disease were combined for analysis, a statistically significant excess of cases occurred among the vaccinees. We concluded that BCG vaccination had no protective effect on the subsequent development of cancer in this population. The slight excess of cases of lymphosarcoma and Hodgkin's disease among the vaccinees raised the possibility that BCG may have had an adverse effect.

Adolescent↗