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<p>Neoantigen vaccines have become an important direction in cancer immunotherapy because mutation-derived tumor antigens can induce highly specific T-cell responses while minimizing immune tolerance associated with tumor-associated antigens. However, their therapeutic performance remains limited by several delivery-related barriers, including rapid antigen degradation, insufficient lymphatic trafficking, weak dendritic-cell activation, and inefficient cross-presentation. Nanotechnology provides flexible strategies to overcome these limitations. This review first summarizes the major delivery mechanisms by which nanocarriers enhance neoantigen presentation and T-cell priming, followed by recent preclinical and clinical advances in neoantigen nanovaccine platforms. Beyond these advances, we highlight the heterogeneity of clinical outcomes across different vaccine platforms and emphasize that vaccine-induced immunogenicity does not always translate into objective clinical benefit. We then analyze major translational bottlenecks, including prolonged neoantigen identification, tumor heterogeneity and neoantigen loss, formulation variability, manufacturing scalability, quality control, and tumor microenvironment-mediated immune resistance. Emerging strategies, including artificial intelligence-assisted neoantigen prioritization, broad-spectrum antigen induction, immunogenicity enhancement, RNA and nanocarrier platform optimization, rational combination therapy, clinically relevant model validation, and biomarker-driven patient stratification, are further discussed. Finally, we propose that future development should integrate rational nanocarrier design with patient stratification, tumor microenvironment modulation, large-scale multicenter clinical validation, standardized manufacturing, and robust potency evaluation. This review aims to provide a translational perspective for the rational development of next-generation neoantigen nanovaccines with improved efficacy, safety, and clinical feasibility.</p> Graphical abstract <p></p>

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Neoantigen nanovaccines for cancer immunotherapy: design strategies, translational bottlenecks, and clinical prospects

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月1日

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  • Mengqi Sun,
  • Liang Xiao,
  • Yongqiang Yu

摘要

Neoantigen vaccines have become an important direction in cancer immunotherapy because mutation-derived tumor antigens can induce highly specific T-cell responses while minimizing immune tolerance associated with tumor-associated antigens. However, their therapeutic performance remains limited by several delivery-related barriers, including rapid antigen degradation, insufficient lymphatic trafficking, weak dendritic-cell activation, and inefficient cross-presentation. Nanotechnology provides flexible strategies to overcome these limitations. This review first summarizes the major delivery mechanisms by which nanocarriers enhance neoantigen presentation and T-cell priming, followed by recent preclinical and clinical advances in neoantigen nanovaccine platforms. Beyond these advances, we highlight the heterogeneity of clinical outcomes across different vaccine platforms and emphasize that vaccine-induced immunogenicity does not always translate into objective clinical benefit. We then analyze major translational bottlenecks, including prolonged neoantigen identification, tumor heterogeneity and neoantigen loss, formulation variability, manufacturing scalability, quality control, and tumor microenvironment-mediated immune resistance. Emerging strategies, including artificial intelligence-assisted neoantigen prioritization, broad-spectrum antigen induction, immunogenicity enhancement, RNA and nanocarrier platform optimization, rational combination therapy, clinically relevant model validation, and biomarker-driven patient stratification, are further discussed. Finally, we propose that future development should integrate rational nanocarrier design with patient stratification, tumor microenvironment modulation, large-scale multicenter clinical validation, standardized manufacturing, and robust potency evaluation. This review aims to provide a translational perspective for the rational development of next-generation neoantigen nanovaccines with improved efficacy, safety, and clinical feasibility.

Graphical abstract