Yang He, Xue Yanpeng, Jiang Qing, Tian Qingqing, Xu Jiayi, Li Jixuan, Yang Quan, Du Mingdong, Yang Teng, Wei Xingwang, Zhao Mei, Yan Tao, Chen Xin, Li Lixian
Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China; Key Colleges and Universities Laboratory of Neurosurgery in Heilongjiang Province, Harbin 150001, Heilongjiang Province, China; Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin 150001, Heilongjiang Province, China.
Department of Pharmacy, Sanya Central Hospital (The Third People's Hospital of Hainan Province), Sanya 572000, China.
Int Immunopharmacol. 2025 Feb 6;147:113856. doi: 10.1016/j.intimp.2024.113856. Epub 2024 Dec 30.
The tumor microenvironment (TME), with hallmark features of hypoxia and immunosuppression, plays a crucial role in the progression of various solid tumors. However, the intricate interplay between tumor hypoxia and the formation of tumor immune microenvironment in glioma remains incompletely understood.
In the present study, we initially identified genes associated with tumor hypoxia and the immune microenvironment through GSEA and IMMPORT database analysis. We subsequently identified hypoxia- and immune-related genes associated with glioma prognosis through further cross-analysis and multidatabase integrated analysis. HSPA5 was ultimately identified as a potential target gene related to the formation of the hypoxic microenvironment and immune microenvironment in glioma. Furthermore, we conducted MTT, colony formation, EdU, migration and invasion assays and intracranial orthotopic tumor model analysis to further evaluate the impact of interfering with HSPA5 expression on the hypoxic and immune microenvironments of glioma.
We found that HSPA5 is highly expressed in glioma cells and tissues and is associated with a poor prognosis. Further investigation revealed that hypoxia promotes the malignant biological characteristics of glioma and reshaping the Immunosuppressive phenotype of tumor-associated macrophages (TAMs) through upregulation of the HIF-1α/HSPA5 axis. Silencing HSPA5 alleviated glioma hypoxia tolerance and induced the polarization of TAMs toward the M1 phenotype. The induced macrophages could exhibit a tumor-suppressive effect.
These observations suggest that HSPA5 upregulation promotes glioma progression by inducing hypoxia tolerance and reshaping the Immunosuppressive phenotype of TAMs. Therefore, targeting HSPA5 may be a novel therapeutic strategy for glioma.
肿瘤微环境（TME）具有缺氧和免疫抑制的标志性特征，在各种实体瘤的进展中起关键作用。然而，胶质瘤中肿瘤缺氧与肿瘤免疫微环境形成之间复杂的相互作用仍未完全阐明。
在本研究中，我们最初通过基因集富集分析（GSEA）和免疫肿瘤学分子图谱数据库（IMMPORT）分析，鉴定了与肿瘤缺氧和免疫微环境相关的基因。随后，通过进一步的交叉分析和多数据库综合分析，鉴定了与胶质瘤预后相关的缺氧和免疫相关基因。热休克蛋白家族A（Hsp70）成员5（HSPA5）最终被确定为与胶质瘤缺氧微环境和免疫微环境形成相关的潜在靶基因。此外，我们进行了MTT、集落形成、5-乙炔基-2'-脱氧尿苷（EdU）、迁移和侵袭实验以及颅内原位肿瘤模型分析，以进一步评估干扰HSPA5表达对胶质瘤缺氧和免疫微环境的影响。
我们发现HSPA5在胶质瘤细胞和组织中高表达，且与预后不良相关。进一步研究表明，缺氧通过上调缺氧诱导因子-1α（HIF-1α）/HSPA5轴促进胶质瘤的恶性生物学特性，并重塑肿瘤相关巨噬细胞（TAM）的免疫抑制表型。沉默HSPA5可减轻胶质瘤的缺氧耐受性，并诱导TAM向M1表型极化。诱导的巨噬细胞可表现出肿瘤抑制作用。
这些观察结果表明，HSPA5上调通过诱导缺氧耐受性和重塑TAM的免疫抑制表型促进胶质瘤进展。因此，靶向HSPA5可能是一种新的胶质瘤治疗策略。
