荧光导航下双靶向纳米粒子介导的光热&Tregs清除治疗对胃癌转移淋巴结免疫抑制微环境的调控

Infiltrated regulatory T cells (Tregs) in metastatic lymph nodes of gastric cancer, contribute primarily to the tumour immune-suppression，immune escape and recurrence of lymph node after operation. Although, traditional methods to deplete Tregs have been proved to be the most promising strategy to enhance the therapeutic effect against tumors, the lethal side effect restricts their clinical application. Thus, whether or not to selectively remove Tregs in the metastatic lymph nodes is the key to the application of the technique of immune checkpoints blockade in the treatment of metastatic lymph nodes. In this project, we proposed a novel method of immuno-photothermal therapy (IPTT) to selectively deplete the infiltrated Tregs in metastatic lymph nodes by anti-CD25 antibody and fluorescent targeting functional groups of gastric cancer cells modified CuS NPs, which were loaded in gelatin sensitive to the microenvironment MMP, to construct a dual target controlled release of "cluster" gelatin nanofluorescence particles. The composite particles could be clustered in metastatic lymph nodes. Under Near infrared laser irradiation, Tregs and gastric cancer cells could be selectively removed to relieve the immunosuppressive microenvironment of metastatic lymph nodes and to prevent nodal recurrence after treatment. This project combined targeted delivery of nanoparticles, real-time intraoperative imaging, selective photothermal therapy and tumor immunotherapy, and established a new type of nanoparticle photothermal therapy system to delete Tregs and tumor cells in lymph nodes. We hope our strategy can play a vital role in preventing and inhibiting lymph node recurrence after operation of gastric cancer.

瘤内调节性T细胞（Tregs）是重要的免疫检查点，通过抑制肿瘤免疫功能，Tregs在肿瘤细胞免疫逃逸中发挥了关键作用，是转移淋巴结术后复发的重要因素。传统注射抗体方法因不能针对性清除瘤内Tregs而引发自身免疫反应。因此，能否选择性清除Tregs是免疫检查点抑制技术应用于转移淋巴结治疗的关键。本项目选择有优异光热转换能力的CuS纳米粒子，分别在其表面修饰靶向Tregs的CD25单抗和胃癌细胞的荧光基团，并共同负载于对肿瘤微环境MMP敏感的明胶中，制备出双靶向“集束型”明胶复合荧光纳米粒子。该复合粒子可以靶向聚集于转移淋巴结，释放其负载的微粒，在激光照射下，选择性清除Tregs和胃癌细胞，解除转移淋巴结的免疫抑制微环境。本项目将纳米粒子靶向投递，术中成像，选择性光热治疗，肿瘤免疫治疗有机结合，建立定点清除转移淋巴结内Tregs和肿瘤细胞的新型纳米光热免疫治疗体系，为防范淋巴结复发提供新思路。

瘤内调节性T细胞（Tregs）是重要的免疫检查点，通过抑制肿瘤免疫功能，Tregs在肿瘤细胞免疫逃逸中发挥了关键作用，是转移淋巴结术后复发的重要因素。传统注射抗体方法因不能针对性清除瘤内Tregs而引发自身免疫反应。因此，能否选择性清除Tregs是免疫检查点抑制技术应用于转移淋巴结治疗的关键。.我们成功构建有具有光热转换能力的纳米粒子，在其表面修饰靶向Tregs的CD25单抗，在激光照射下，该纳米粒子能够选择性清除Tregs，解除免疫抑制微环境。本项目将纳米粒子靶向投递，选择性光热治疗，肿瘤免疫治疗有机结合，建立定点清除Tregs的新型纳米光热免疫治疗体系，为防范肿瘤复发提供新思路。