靶向抑制USP7促进巨噬细胞M1表型转化增加鼻咽癌放疗敏感性的机制研究

放疗抵抗是鼻咽癌（NPC）治疗失败的主要原因之一。肿瘤相关巨噬细胞（TAMs）以M2型为主，其参与肿瘤放疗抵抗。泛素特异性蛋白酶（USPs）对TAMs极化的影响未见报道。对比M1/M2型巨噬细胞内39种USPs的转录水平，我们发现USP7表达差异最显著，抑制USP7可活化MAPK通路，重塑M2向M1型转化，增加NPC细胞放疗敏感性。进一步研究发现，USP7可与Birc6互作，过表达Birc6能部分逆转抑制USP7导致的M1型极化。据此提出假说：抑制USP7可促进Birc6蛋白降解，激活MAPK通路介导TAMs向M1型转化，增加NPC放疗敏感性。本研究拟明确USP7与Birc6相互作用及活化MAPK通路的分子机制，并利用人源化MISTRG小鼠模型阐明抑制USP7对免疫微环境及NPC放疗敏感性的影响。本研究有望为NPC放疗增敏提供新的分子靶点，具有重要理论价值与临床意义。

Radiotherapy resistance is mainly responsible for the failure of nasopharyngeal carcinoma (NPC) treatment. It has been demonstrated that M2 macrophages, as the main type of tumor-associated macrophages (TAMs), play an important role in tumor radioresistance. Our previous work revealed that USP7 had the greatest expression variation by comparing the transcriptional profiles of USPs gene family members in the M1 and M2 macrophages, and inhibiting USP7 with the inhibitor P5091 could activate MAPK pathway and reprogram TAMs from M2 to anti-tumor M1 phenotype, thus increasing the radiosensitivity of NPC. Meanwhile, USP7 interacted with Birc6, and the overexpression of Birc6 could partially reverse M1 polarization caused by USP7 knockout. Therefore, we hypothesize that inhibiting USP7 may promote the degradation of Birc6, activate MAPK pathway, reprogram TAMs to M1 macrophages and improve the radiosensitivity of NPC. Based on the above, this research is aimed at further proving the interaction between USP7 and Birc6, clarifying the molecular mechanism of MAPK pathway activation and exploring the effects of USP7 inhibition on tumor microenvironment and NPC radiosensitivity via a humanized MISTRG mouse model. Furthermore, a novel molecular target for NPC radiotherapy could be established in a promising manner, paving the way for NPC treatment.