Source data of Neoantigens combined with in situ cancer vaccination induce personalized immunity and reshape the tumor microenvironment

Neoantigen (nAg) vaccines can induce anti-tumor specific immunity, and tumor killing promotes further antigen diffusion, which is expected to improve prognosis. However, the mutation of cancer cells under the selective pressure of vaccines and the immunosuppressive tumor microenvironment make the therapeutic effect unsatisfactory. Here, we develop a nanovaccine (nAg-MRDE/Mn) that can deliver nAg and induce in situ cancer vaccination to synergistically promote a personalized immune response, enhance antigen diffusion, and improve the microenvironment by modulating immunosuppressive cells and activating the innate immune response. Experiments show that neoantigens are presented by dendritic cells and expressed by T cells, which cooperate with in situ vaccination to stimulate specific immunity. Cells involved in immunosuppression, such as M2 macrophages and regulatory T cells, are down-regulated, while M1 macrophages and natural killer cells are increased. In addition, the hydrogel loaded with chemokines and nAg-MRDE/Mn inhibits postoperative tumor recurrence, and the combination of nAg-MRDE/Mn and αPD-1 improves the therapeutic effect of αPD-1. This study validates the clinical potential of this strategy and provides ideas for improving neoantigen vaccines.

新抗原（Neoantigen, nAg）疫苗可诱导抗肿瘤特异性免疫，而肿瘤杀伤作用能促进抗原进一步扩散，有望改善预后。然而，疫苗选择压力下癌细胞的突变以及免疫抑制性肿瘤微环境导致治疗效果不尽如人意。在此，我们开发了一种纳米疫苗（nAg-MRDE/Mn），可递送nAg并诱导原位癌症疫苗接种，通过调控免疫抑制细胞和激活固有免疫应答，协同促进个性化免疫反应、增强抗原扩散并改善微环境。实验表明，新抗原由树突状细胞呈递并由T细胞表达，与原位疫苗接种协同刺激特异性免疫。参与免疫抑制的细胞（如M2型巨噬细胞和调节性T细胞）被下调，而M1型巨噬细胞和自然杀伤细胞数量增加。此外，负载趋化因子和nAg-MRDE/Mn的水凝胶可抑制术后肿瘤复发，且nAg-MRDE/Mn与αPD-1联合使用能提升αPD-1的治疗效果。本研究验证了该策略的临床潜力，并为优化新抗原疫苗提供了思路。