基于STATs磷酸化诱导TAMs重塑探究黄芪多糖协同卡博替尼抗胃肠间质瘤耐药机制

“癌基因”的内在驱动和“肿瘤微环境（TME）”阴阳平衡失调的外在驱动是肿瘤耐药的关键。前期，我们发现卡博替尼能有效克服胃肠间质瘤（GISTs）耐药性突变，然而长期使用耐药问题不可避免。GISTs耐药机制复杂，需贯穿激酶靶点和TAMs双重调控的整体治疗模式。M2型TAMs是GISTs耐药的潜在靶标，卡博替尼杀伤GISTs细胞的同时是否影响TAMs极化尚不明确，中医“扶正”理念指导下的黄芪多糖（APS）可重塑TAMs表型（M2→M1，阴→阳）从而间接抑制肿瘤进展。鉴此提出假说：黄芪多糖协同卡博替尼可通过重塑TAMs表型克服肿瘤耐药性并产生更强的抗肿瘤功效。本项目拟以TAMs重塑为切入点，运用免疫荧光共定位、RNA干扰等关键技术，确证TAMs表型与GISTs耐药的相互作用关系，深入解析TAMs重塑机制，并在细胞水平和动物体内加以验证，为中医中药协同分子靶向药物克服肿瘤耐药提供科学依据。

The internal drive of "oncogene" and the external drive of imbalance of Yin and Yang in "tumour microenvironment (TME)" are the key to drug resistance. Previously, we found that the "old drug" cabozantinib could effectively overcome the drug resistance mutation of gastrointestinal stromal tumours (GISTs), but long-term use of drug resistance is inevitable. The mechanism of drug resistance of GISTs is complex, which needs to run through the dual regulation of kinase target and TAMs. M2 TAMs are potential targets for drug resistance of GISTs. It is not clear whether cabozantinib could affect the polarization of TAMs while killing GISTs cells. Astragalus polysaccharides (APS) under the guidance of "Fu Zheng" concept of traditional Chinese medicine could reshape the phenotype of TAMs (M2 → M1, Yin → Yang) and indirectly inhibit tumour progression. In view of this, we propose a hypothesis that APS synergy with cabozantinib could overcome the drug resistance of tumour and produce stronger anti-tumour effect by reshaping the phenotype of TAMs. This project intends to take TAMs remodeling as the breakthrough point, using immunofluorescence co localization, RNA interference and other key technologies to confirm the interaction between TAMs phenotype and GISTs resistance, deeply analyze the TAMs remodeling mechanism, and verify it at the cell level and animal body, so as to provide scientific basis for traditional Chinese medicine synergy with molecular targeted drugs to overcome tumour resistance.