Abstract：
In situ cancer vaccination is an attractive strategy that stimulates protective antitumor immunity. Cytotoxic T lymphocytes (CTLs) are major mediators of the adaptive immune defenses, with critical roles in antitumor immune response and establishing immune memory, and are consequently extremely important for in situ vaccines to generate systemic and lasting antitumor efficacy. However, the dense extracellular matrix and hypoxia in solid tumors severely impede the infiltration and function of CTLs, ultimately compromising the efficacy of in situ cancer vaccines. To address this issue, a robust in situ cancer vaccine, Au@MnO2 nanoparticles (AMOPs), based on a gold nanoparticle core coated with a manganese dioxide shell is developed. The AMOPs modulated the unfavorable tumor microenvironment (TME) to restore CTLs infiltration and function and efficiently induced immunogenic cell death. The Mn2+-mediated stimulator of the interferon genes pathway can be activated to further augment the therapeutic efficacy of the AMOPs. Thus, the AMOPs vaccine successfully elicited long-lasting antitumor immunity to considerably inhibit primary, recurrent, and metastatic tumors. This study not only highlights the importance of revitalizing CTLs efficacy against solid tumors but also makes progress toward overcoming TME barriers for sustained antitumor immunity.
摘要：
原位癌疫苗接种是刺激保护性抗肿瘤免疫的有吸引力的策略。细胞毒性T淋巴细胞（CTL）是适应性免疫防御的主要介质，在抗肿瘤免疫反应和建立免疫记忆中起关键作用，因此对于原位疫苗产生系统性和持久的抗肿瘤功效极为重要。然而,实体瘤中致密的细胞外基质和缺氧严重阻碍了CTL的浸润和功能，最终损害原位癌疫苗的功效。为了解决这个问题，一种强大的原位癌疫苗，Au@MnO2纳米颗粒（AMOPs），开发了基于包覆有二氧化锰壳的金纳米粒子核。AMOP调节不利的肿瘤微环境（TME）以恢复CTL的浸润和功能，并有效诱导免疫原性细胞死亡。干扰素基因途径的Mn2+介导的刺激物可以被激活以进一步增强AMOPs的治疗功效。因此，AMOPs疫苗成功地引发了持久的抗肿瘤免疫，大大抑制了原发，经常性,和转移性肿瘤。这项研究不仅强调了恢复CTL对实体瘤的功效的重要性，而且在克服TME障碍以实现持续的抗肿瘤免疫方面取得了进展。
