This work ¹ was motivated by a persistent gap in the field: strong immunogenicity does not consistently translate into durable clinical benefit. Early clinical studies show that neoantigen mRNA vaccines can induce CD8⁺ and CD4⁺ T-cell responses and expand tumor-reactive clones, particularly in melanoma and NSCLC, yet clinical efficacy remains heterogeneous  ^2,3. This disconnect between immune activation and sustained tumor control defined the central focus of the paper. Importantly, the work also highlights that the antigen landscape itself is broader than previously assumed, extending beyond mutation-derived epitopes to include cryptic peptides generated from non-canonical translation events.

• A continuum of antigen and vaccine strategies

A central contribution of this review is the structured classification of antigen and vaccine strategies. Tumor-specific antigens (TSAs), tumor-associated antigens (TAAs), shared neoantigens, and hybrid constructs represent distinct but interconnected approaches ⁴. Personalized TSA-based vaccines provide maximal specificity but are constrained by manufacturing timelines (6–8 weeks), cost, and tumor heterogeneity ⁵. Shared and off-the-shelf vaccines targeting recurrent driver mutations such as KRAS and TERT enable scalable deployment, while hybrid designs combine individualized and recurrent antigens to increase epitope diversity and reduce immune escape ^6,7. Notably, the inclusion of cryptic neoantigens, derived from non-canonical ORFs, intronic regions, and lncRNAs, expands the targetable repertoire, particularly in tumors with low mutational burden ^8,9.

• Immunoengineering and functional optimization

A key advance highlighted in this work is the shift toward functional immunogenic optimization. Improvements in antigen prioritization, through WES, RNA sequencing, and immunopeptidomics, have enhanced neoepitope identification, although validation remains essential due to prediction inaccuracies ¹⁰. At the molecular level, mRNA engineering strategies, including codon optimization, nucleoside modification (e.g., m¹Ψ), UTR tuning, and multi-epitope construct design, have improved antigen expression and presentation. Parallel advances in LNP delivery systems and targeting strategies have enhanced dendritic cell uptake and T-cell priming, contributing to more consistent immune responses across diverse HLA backgrounds ^11,12.

• Adaptive vaccination and dynamic antigen targeting

A major forward-looking aspect of the paper is the concept of adaptive vaccination. Tumor evolution under immune pressure frequently results in antigen loss and clonal escape, particularly when targeting subclonal mutations. The integration of ctDNA monitoring enables real-time tracking of tumor dynamics and creates the possibility of iterative vaccine redesign during treatment ^13,14. This approach shifts the paradigm from static vaccine constructs to dynamic, evolution-informed immunotherapy strategies capable of adjusting to tumor heterogeneity over time.

• Future direction

The next phase of neoantigen mRNA vaccination will be defined by adaptability and integration. Tumor evolution and immune editing continue to limit the durability of fixed vaccine designs, making dynamic strategies increasingly important ¹⁵. Approaches incorporating ctDNA monitoring may enable real-time tracking of clonal changes and iterative updating of antigen composition during treatment. At the same time, hybrid and modular vaccine platforms that combine TSAs, shared neoantigens, and cryptic peptides from non-canonical translation offer a practical path to balance precision with scalability ^16,17. Advances in delivery systems and immune modulation will further refine how these vaccines engage both innate and adaptive immunity ¹⁸. Clinically, their impact will depend on rational positioning, particularly in adjuvant and minimal residual disease settings, and integration with checkpoint blockade to overcome immune suppression ^19,20.

• Summar

Overall, this work positions neoantigen mRNA vaccination as a flexible and evolving therapeutic framework rather than a single platform. By expanding the antigen landscape to include diverse classes: TSAs, TAAs, shared, hybrid, and cryptic neoantigens, and integrating advances in antigen prioritization, mRNA engineering, and delivery, the field is moving toward more functionally optimized and clinically adaptable strategies. The central insight is that durable clinical benefit will depend not only on antigen specificity, but on aligning molecular design, immune activation, and clinical context within a coordinated translational approach.

• About Authors

Saber Imani is an independent Assistant Professor focused on mRNA-based cancer vaccines and translational oncology, with research centered on elucidating the molecular mechanisms underlying cancer and viral diseases, particularly in the context of immune checkpoint inhibitors (ICIs) and immunotherapy-driven treatment strategies. His work integrates mechanistic biology with therapeutic development, aiming to reprogram the tumor microenvironment to enhance anti-tumor immune responses and advance next-generation cancer therapies, including ICI-based interventions and mRNA vaccine platforms, with the broader goal of improving clinical outcomes and addressing critical challenges in oncology.

Parham Jabbarzadeh Kaboli is a cancer researcher based in the United States, specializing in translational pharmacology and tumor biology. He earned his Ph.D. in Pharmacology from Universiti Putra Malaysia in 2018 and has since developed a strong research profile, with an h-index of 30 and over 2,600 citations. His work focuses on the development of targeted therapeutic strategies and the mechanistic understanding of drug resistance in cancer, particularly in breast cancer. Dr. Kaboli has contributed to more than 40 peer-reviewed publications and has mentored emerging scientists across diverse academic environments. His research journey spans multiple international institutions, including Malaysia, China, Taiwan, and the United States, providing him with a broad and integrative scientific perspective. During his postdoctoral training at China Medical University in Taiwan, he conducted advanced studies on the c-MET receptor tyrosine kinase, exploring its role in tumor progression and therapeutic resistance. He is currently a Visiting Scientist at Aptegen LLC in York, Pennsylvania, where he is engaged in research at the interface of molecular targeting and translational innovation. Looking forward, Dr. Kaboli aims to establish an independent research program focused on overcoming therapeutic resistance in solid tumors through the integration of immunotherapy and clinically relevant strategies. He remains deeply committed to scientific mentorship, interdisciplinary collaboration, and advancing cancer research across global boundaries.

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