基于糖代谢重编程重塑肿瘤微环境探讨紫草素调控小细胞肺癌免疫应答的机制研究

免疫治疗在小细胞肺癌中取得了突破性进展，但有效率仍较低，获益时间短，研究表明这可能与浸润在肿瘤微环境中的巨噬细胞密切相关。M1 型巨噬细胞是通过无氧糖酵解途径获取能量，M2 型巨噬细胞则通过有氧糖酵解途径获取能量，糖代谢方式的改变影响着巨噬细胞的不同极化状态及其功能。研究发现通过特定的手段或药物，诱导M2型向M1 型转化，可重塑肿瘤免疫微环境。我们前期发现紫草素有改变癌细胞糖代谢重编程的作用，结合文献和前期工作，我们提出假说：紫草素可改变小细胞肺癌细胞糖代谢重编程，进而促使巨噬细胞发生极化，M2型转化为M1型，重塑小细胞肺癌免疫微环境，小细胞肺癌提高免疫应答。C-Myc是代谢调控免疫的关键基因。本项目通过在细胞和动物水平紫草素可改变癌细胞代谢重编程，检测巨噬细胞的表型转化。研究结果有助于明确紫草素从糖代谢重编程角度重塑肿瘤免疫微环境的作用及机制，为中医药提高免疫治疗应答提供新的研究思路。

Pd-1/pd-l checkpoint inhibitors have made a breakthrough in the treatment of small-cell lung cancer(SCLC), but the respond is still low and the benefit time is short, which may be closely related to macrophages infiltrating in the tumor microenvironment.M1 macrophages obtain energy through anaerobic glycolysis, while M2 macrophages obtain energy through aerobic glycolysis. Changes in glucose metabolism patterns affect different polarization states and functions of macrophages. Studies have found that macrophages in tumor microenvironment can be remodeled, and the transformation from M2 to M1 can be induced by specific means or drugs to reshape tumor immune microenvironment. Our preliminary results showed shikonin change glucose metabolism reprogramming in SCLC cells, combined with the literature and previous work, we propose a hypothesis: shikonin can change glucose metabolism reprogramming in SCLC, prompting the macrophage polarization, converting M2 to M1, regulating immune microenvironment, increasing immune response. C-myc is the key gene. In this study, the macrophages phenotypic and indicators of glucose metabolism would be detected before and after shikonin intervention at the cellular and animal levels. The results will be helpful to clarify the mechanism of shikonin in remodeling tumor immune microenvironment based on glycometabolism reprogramming, and provide new research ideas for TCM to improve immune response.