A great potential of tumor vaccine-based immunotherapy has been emerged; however, the low cross-presentation of tumor antigens, intrinsic immunosuppressive signaling of dendritic cells (DCs) and the immunosuppression in tumor microenvironment (TME) hindered the progress of tumor vaccine. In this article, approaches employed heterocyclic lipid nanoparticles (LNP) as a tumor vaccine and signal transduction and activator of transcription 3 (STAT3) siRNA carrier as well as a “self-adjuvant” by targeting draining lymph node (DLN) and stimulating stimulator of interferon genes (STING)-mediated type I interferon (IFN) innate immune response were proposed. Model antigens ovalbumin peptide 257–264 (OVA) were cross-presented to activate T cells; STAT3 siRNA acted synergistically with OVA to improve DCs maturation, enhance antigen presentation and abrogate immunosuppressive TME; heterocyclic lipids induced the production of type I IFN via activating the STING pathway. Compared to DLin-MC3-DMA LNP, heterocyclic LNPs, especially A18-LNP, targeted DLN, delivered much OVA and STAT3 siRNA into cytoplasm of antigen-presenting cells (APCs, mainly DCs), activated STING pathway, promoted DCs maturation and antigen presentation, abrogated immunosuppression in TME, therefore, leading to robust anti-cancer response. Thus, heterocyclic LNPs efficiently delivered tumor vaccine and STAT3 siRNA and simultaneously activated the immune system through DLN-targeted and STING pathway, provided better antitumor effects, suggesting a promising strategy for cancer immunotherapy.

基于肿瘤疫苗的免疫治疗的巨大潜力已显现；然而，肿瘤抗原的低交叉呈递、树突状细胞（DC）固有的免疫抑制信号以及肿瘤微环境（TME）的免疫抑制阻碍了肿瘤疫苗的进展。在这篇文章中，方法采用杂环脂质纳米粒子（LNP）作为肿瘤疫苗和信号转导和转录激活剂3（STAT3）siRNA载体，以及通过靶向引流淋巴结（DLN）和刺激肿瘤细胞的刺激物作为“自我佐剂”。提出了干扰素基因（STING）介导的 I 型干扰素（IFN）先天免疫反应。模型抗原卵清蛋白肽 257-264 (OVA) 交叉呈递以激活 T 细胞；STAT3 siRNA 与 OVA 协同作用，促进 DC 成熟，增强抗原呈递并消除免疫抑制 TME；杂环脂质通过激活 STING 途径诱导 I 型干扰素的产生。与DLin-MC3-DMA LNP相比，杂环LNP，尤其是A18-LNP，靶向DLN，将大量OVA和STAT3 siRNA递送到抗原呈递细胞（APC，主要是DC）的细胞质中，激活STING通路，促进DC成熟和抗原呈递，因此消除了 TME 中的免疫抑制，从而产生强大的抗癌反应。因此，杂环LNPs有效地递送肿瘤疫苗和STAT3 siRNA，同时通过DLN靶向和STING通路激活免疫系统，提供更好的抗肿瘤效果，这为癌症免疫治疗提供了一种有前景的策略。