5-氟尿嘧啶（5-FU）在晚期结直肠癌治疗中占据重要地位，但耐药问题亟待解决。文献报道和我们前期工作都发现肿瘤微环境中NLRP3炎症小体出现活化并可能导致5-FU耐药，但详细机制不明。本项目拟进一步研究肿瘤微环境中炎性细胞（髓系来源抑制性细胞，巨噬细胞）与肿瘤细胞交互作用中NLRP3炎症小体活化的机制，探讨穿心莲内酯调控不同细胞内炎症小体活化对5-FU耐药的影响及整体动物试验二者联用的效果；进一步综合运用分子、细胞生物学方法及靶点垂钓、表面等离子共振、等温量热滴定、分子对接等技术阐明穿心莲内酯抑制炎症小体活化的分子机制及作用的靶蛋白，并确证靶蛋白对炎症小体活化的作用及其对5-FU耐药的影响。最后通过临床试验考察穿心莲内酯和5-FU联用治疗晚期结肠癌的有效性和安全性，并进行分子机制的验证。该项目不仅为肿瘤耐药的逆转提供了新的理论依据，还为临床上许多以5-FU为基石的肿瘤治疗方案提供新的选择。

5-fluorourracil (5-FU) is still the most important chemotherapeutic drug used for the treatment of colon cancer, but still it is urgent to solve the problem of 5-FU resistance. According to the report by others and our own study, we found that the NLRP3 inflammasome was activated in the tumor microenvironment and may lead to resistance to 5-FU but the detail mechanism is still unclear. The study intends to investigate mechanism of inflammasome activation and effect on 5-FU resistance in inflammatory cells (such as Myeloid-derived suppressor cells and macrophages) and tumor cell interactions in the tumor microenvironment and examine the synergy of andrographolide and 5-FU in anti-cancer proliferation and the mechanism of drug resistance reversal. Further, we will tryting to identify the target of andrographolide in the perspective of autophagy mediated-NLRP3 inhibition. Finally, we will design the clinical trail to verify the efficacy and safety of combining andrographolide with 5-FU for patients with advanced colorectal cancer, and confirm the molecular mechanism. The project not only provides a new theoretical basis of reversing tumor resistance, also supply with new option for many clinical treatment of 5-FU as the cornerstone.