Neoantigen in cancer immunotherapy: mechanism, therapeutic strategies and future perspectives.

Mechanism of neoantigen generation and advances in neoantigen-based immunotherapies in colorectal cancer

Take Five: harmonization in personalized cancer vaccines for cancer immunotherapy.

Precision medicine provides a therapeutic framework that addresses the interindividual diversity in tumor genetics, immunological determinants of disease, and immune responsiveness. Among precision approaches, personalized cancer vaccines (PCVs) have gained attention as a promising strategy for inducing tumor-specific immunity by identifying patient-derived neoantigens. Despite encouraging clinical outcomes, the development of PCVs faces major challenges in optimizing antigen selection, delivery, immune activation, and clinical translation. This Review summarizes current advances in PCV research, covering tumor antigen classification, neoantigen prediction algorithms, and the evolution of delivery technologies such as peptide, dendritic cell, DNA, and mRNA-lipid nanoparticle platforms. We highlight the advantages of mRNA-lipid nanoparticle systems that enable rapid manufacturing, potent antigen expression, and integration with immunostimulatory cytokines. Furthermore, we discuss emerging combination strategies involving cytokine engineering and T cell modulation that provide new opportunities to enhance immunogenicity and therapeutic efficacy. Ultimately, we propose that the future maturation of PCVs will require a coordinated process across five interconnected dimensions: (1) advances in neoantigen prediction technologies, (2) rapid delivery of PCVs to patients, (3) an increase in anticancer efficacy through combination therapy strategies, (4) establishment of cost-effective manufacturing processes, and (5) regulatory innovation. In this Review, we conceptualize this multidimensional alignment as "Take Five," a unifying framework to bring precision, rhythm, and balance to next-generation cancer immunotherapy.

Tumor-induced immune escape mechanisms and translational immunotherapeutic strategies.

Tumor-induced immune evasion is a critical mechanism that promotes resistance to anticancer therapies and facilitates cancer progression. Notwithstanding the emergence of immunotherapies, especially immune checkpoint inhibitors (ICIs) and adoptive cell therapies, several cancers show resistance against such therapeutic interventions by adopting various methods of immune evasion. These include alterations to the tumor microenvironment (TME), infiltration of immunosuppressive cells, overexpression of inhibitory checkpoint molecules, and modified antigen presentation. This study provides a comprehensive assessment of the cellular and molecular principles behind immune evasion, as well as novel and established strategies for its prevention. The mechanisms, clinical implications, and limitations of significant therapeutic modalities, including checkpoint blockade, CAR-T cell therapy, cancer vaccines, and oncolytic virotherapy, are addressed. Particular emphasis is placed on combinatorial approaches, TME reprogramming, and next-generation targets like LAG-3, TIM-3, and TIGIT. The research examines the potential of predictive biomarkers, including PD-L1, Tumor Mutational Burden (TMB), Microsatellite Instability (MSI), and the microbiome, to guide personalized immunotherapy. Overcoming resistance and achieving enduring responses requires the integration of immunological insights with high-throughput molecular profiling and adaptive clinical trial design as the subject develops. The efficacy of immunotherapies across many cancer types may be enhanced by adopting a systems-level perspectives on tumor-immune interactions. Ultimately, restoring effective antitumor immunity with new, customized therapies is a crucial advancement in current oncology.

Personalized cancer vaccines: bridging immune-oncology and precision medicine for advanced therapeutics

Despite advancements in therapeutic cancer vaccines, clinical translation has been hindered by limited efficacy, with Sipuleucel-T remaining the only FDA-approved therapeutic cancer vaccine to date. However, recent advances in personalized mRNA vaccines, such as Moderna’s mRNA-4157 and BioNTech’s autogene cevumeran, have demonstrated significant reductions in recurrence risk and improved survival across several cancer types, renewing optimism in the field. Personalized cancer vaccines leverage patient-specific tumor antigens to initiate potent and targeted immune responses. This review outlines various classes of personalized vaccines, including DNA-, mRNA-, peptide-, dendritic cell-, and whole-cell-based platforms, and examines the immunological challenges they face, such as tumor heterogeneity, immunosuppressive microenvironments, and inadequate immune memory. To address these limitations, both conventional and nanotechnology-enhanced delivery systems have been developed. Notably, nanovaccines constructed from lipid-polymer hybrids, biomimetic membranes, and stimulus-responsive materials enable codelivery of neoantigens and immunostimulatory agonists, promoting enhanced lymph node targeting, dendritic cell activation, and antigen cross-presentation. Furthermore, biomimetic formulations incorporating autologous tumor membranes preserve native antigenic diversity and allow dynamic adaptation to evolving tumors. When integrated with artificial intelligence for antigen selection and multiomics for patient stratification, these platforms accelerate vaccine design and improve precision. Combination regimens with immune checkpoint inhibitors or other agents further potentiate efficacy and promote durable antitumor immunity. Increasing clinical evidence, especially in melanoma and pancreatic cancer, underscores the potential of these strategies to induce long-term protection and reduce recurrence. Overall, next-generation personalized cancer vaccines are advancing the transition from reactive treatment to proactive, precision-controlled cancer immunotherapy.

Mechanistic biomarkers for cancer vaccine development: from cancer cell biology to neoantigen-guided precision immunotherapy

Cancer vaccines have resurged in oncology because they address a central question in precision medicine: whether the molecular identity of a tumor can be converted into an immune target that is both specific and clinically useful. Preventive vaccines against oncogenic viruses have already shown that immune intervention can reduce the burden of virus-associated cancers. Therapeutic cancer vaccines face a more difficult task, because established tumors arise from self-tissues, change over time, and often acquire mechanisms that limit antigen presentation, T-cell entry, or immune-mediated killing. This review examines cancer vaccines as biomarker-driven tools within precision oncology. The focus is not only on vaccine platforms, but on the biological requirements that make an antigen suitable for therapeutic targeting. Tumor-specific mutations, viral antigens, recurrent driver alterations, frameshift peptides, cancer-testis antigens, and personalized neoantigens may all provide vaccine targets, but their presence alone is not enough. A clinically relevant vaccine antigen should be expressed by tumor cells, processed and presented through HLA molecules, recognized by functional T cells, and sufficiently retained during tumor evolution. This distinction is particularly important because sequencing and computational prediction now generate many candidate neoantigens whose immunological relevance still requires experimental confirmation. Particular attention is given to antigen-presentation defects, clonal and subclonal heterogeneity, tumor microenvironment barriers, circulating tumor DNA-defined minimal residual disease, and immune-response monitoring. Colorectal cancer is used as a working model because microsatellite instability-high/mismatch repair-deficient tumors, microsatellite-stable tumors with immune-resistant features, and recurrent alterations in MMR genes, KRAS, BRAF, adenomatous polyposis coli, and TP53 illustrate how cancer-cell signaling, neoantigen generation, tumor microenvironment remodeling, and patient stratification intersect. Overall, cancer vaccines are unlikely to become universal stand-alone treatments for advanced solid tumors. Their most credible role may emerge in molecularly selected patients, adjuvant therapy, minimal residual disease, virus-associated malignancies, and rational combinations with checkpoint inhibitors or tumor microenvironment-modulating agents.

Modalities to identify clinically actionable neoantigens.

Immune checkpoint inhibitors (ICIs), which restore antitumor immunity mediated by T cells, have caused a paradigm shift in cancer therapy. However, only a subset of patients achieve durable clinical responses, highlighting the need to better understand the mechanisms that determine antitumor immunity. Cancer-specific neoantigens are considered key determinants of effective immune responses because they are recognized as non-self by T cells and can induce strong immune responses. Accordingly, neoantigens are considered promising targets for cancer vaccines and adoptive cell therapies. Neoantigens have conventionally been considered to arise from somatic mutations and have been identified using whole-exome sequencing (WES). However, the number of neoantigens identified with WES remains limited. In contrast, advances in technology have revealed that peptides derived from various sources, including noncoding regions, are immunogenic and function as neoantigens. In particular, human leukocyte antigen (HLA) ligandome analyses, which enabled the direct identification of peptides presented on HLA molecules in combination with various sequencing technologies, have extended the landscape of neoantigen sources. However, in many cases, the immunogenicity of the identified neoantigen candidates has not been experimentally evaluated. Recently, several experimental platforms have been developed to validate neoantigen immunogenicity, which can be complemented by single-cell RNA/T-cell receptor sequencing to identify tumor-reactive T cell clones. In this review, we summarize current neoantigen identification strategies and discuss the challenges and future perspectives in neoantigen research.