编码免疫刺激分子的 mRNA 的瘤内递送可以通过增强肿瘤和肿瘤引流淋巴结中的局部抗原呈递来启动强大的、全面的抗肿瘤反应，且副作用很小。基于新抗原的 mRNA 纳米疫苗可以通过瘤内注射抑制小鼠黑色素瘤的生长。骨髓源性抑制细胞 (MDSC) 通过分泌活性氧 (ROS) 等免疫抑制剂来抑制抗肿瘤免疫反应。通过静电抑制 STAT3 活性可能会减少 TME 中 MDSC 介导的免疫抑制并促进抗肿瘤免疫反应。在这项研究中，制备了体外转录的编码肿瘤抗原生存素的mRNA，并将其注射到患有皮下结肠癌肿瘤的BALB/c小鼠体内。体内研究表明，肿瘤内生存素mRNA治疗可以诱导抗肿瘤T细胞反应并抑制结肠癌的肿瘤生长。 CD8 T 细胞的耗竭可以显着抑制生存素 mRNA 诱导的抗肿瘤作用。 RT-qPCR 和 ELISA 分析表明，生存素 mRNA 处理导致受体激活核因子-κB 配体 (RANKL) 表达增加。体外实验表明，RANKL可以从小鼠骨髓细胞中诱导MDSCs，并且RANKL诱导的MDSCs可以产生高水平的ROS。 STAT3 抑制剂 stattic 抑制 STAT3 和 NF-κB 信号的激活，从而抑制 RANKL 诱导的 MDSC 的扩增。与单一疗法相比，survivin mRNA 和 statistic 的联合治疗可以显着增强抗肿瘤 T 细胞反应，提高长期生存率并减少免疫抑制的肿瘤微环境。此外，联合治疗导致CT26结肠癌荷瘤小鼠肿瘤细胞增殖水平显着降低，肿瘤细胞凋亡水平显着升高，有利于抑制肿瘤生长并引发释放肿瘤细胞的免疫反应。相关抗原。这些研究探索了瘤内 mRNA 疗法和基于 mRNA 的联合疗法治疗结肠癌，为癌症治疗提供了新思路。版权所有 © 2024。由 Elsevier B.V. 出版。

Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as reactive oxygen species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon cancer tumors. In vivo studies demonstrated that intratumoral survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon cancer. Depletion of CD8+ T cells could significantly inhibit survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon cancer and provide a new idea for cancer therapy.Copyright © 2024. Published by Elsevier B.V.