Gao Wei, Long Xinmiao, Lin Xiang, Deng Kun, Li Danyang, Huang Meng, Wang Xiangyu, Liu Qing, Wu Minghua
The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, China.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
J Adv Res. 2025 May 13. doi: 10.1016/j.jare.2025.05.032.
Temozolomide (TMZ) resistance poses a significant challenge to the treatment of aggressive and highly lethal glioblastomas (GBM). Monocyte-derived Macrophages (MDM) within the tumor microenvironment are key factors contributing to TMZ resistance in GBM. Lactate-mediated histone lysine lactylation (Kla) plays a crucial role in the regulation of tumor progression. However, the mechanism through which MDM-induced Kla expression promotes TMZ resistance in GBM remains unclear.
The objective of this study s to identify a subtype of MDM with therapeutic potential target and to elucidate the mechanisms through which this subtype of MDM contributes to tumor malignant progression and TMZ resistance.
We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics data to evaluate whether mesenchymal (MES) MDM is associated with poor prognosis. By establishing a subtype model of GBM cells for the first time, we validated the mechanism by which MES-MDM promotes subtype conversion of tumor cells. Using patient-derived GBM organoids and an intracranial orthotopic GBM model, we demonstrated that targeting MES-MDM increased GBM sensitivity to TMZ treatment.
We identified a novel MDM subtype, MES-MDM, in the hypoxic niches of the perinecrotic region characterized by high TREM1 expression, which fueled GBM progression. Hypoxia drived MES-MDM signatures by activating ATF3 transcription. MES-MDM facilitated the transition from the NPC to the MES subtype in GBM cells, in which Histone Deacetylase 1 (HDAC1) Kla, induced by the TNF-CELSR2/p65 signaling pathway, promoted this conversion, thereby promoting TMZ resistance. Targeting MES-MDM with TREM1 inhibitory peptides amplified TMZ sensitivity, offering a potential strategy for overcoming resistance to therapy in GBM. Targeting TREM1 enhanced the effectiveness of anti-PD-1 immunotherapy.
This study provides a potential therapeutic strategy for patients with MES-subtype GBM by targeting MES-MDM in combination with TMZ or PD-1 antibody treatment.
替莫唑胺（TMZ）耐药性对侵袭性和高度致命性胶质母细胞瘤（GBM）的治疗构成了重大挑战。肿瘤微环境中的单核细胞衍生巨噬细胞（MDM）是导致GBM中TMZ耐药的关键因素。乳酸介导的组蛋白赖氨酸乳酰化（Kla）在肿瘤进展的调节中起关键作用。然而，MDM诱导的Kla表达促进GBM中TMZ耐药的机制仍不清楚。
本研究的目的是鉴定具有治疗潜力靶点的MDM亚型，并阐明该亚型MDM促进肿瘤恶性进展和TMZ耐药的机制。
我们整合单细胞RNA测序（scRNA-seq）和空间转录组学数据，以评估间充质（MES）MDM是否与预后不良相关。通过首次建立GBM细胞的亚型模型，我们验证了MES-MDM促进肿瘤细胞亚型转化的机制。使用患者来源的GBM类器官和颅内原位GBM模型，我们证明靶向MES-MDM可增加GBM对TMZ治疗的敏感性。
我们在坏死周围区域的低氧微环境中鉴定出一种新的MDM亚型，即MES-MDM，其特征是高表达触发受体表达的髓系细胞1（TREM1），这推动了GBM的进展。缺氧通过激活激活转录因子3（ATF3）转录驱动MES-MDM特征。MES-MDM促进GBM细胞从神经祖细胞（NPC）亚型向MES亚型的转变，其中由肿瘤坏死因子（TNF）-钙黏蛋白表皮生长因子样受体2（CELSR2）/核因子κB（p65）信号通路诱导的组蛋白去乙酰化酶1（HDAC1）Kla促进了这种转化，从而促进了TMZ耐药。用TREM1抑制肽靶向MES-MDM可增强TMZ敏感性，为克服GBM治疗耐药提供了一种潜在策略。靶向TREM1可增强抗程序性死亡蛋白1（PD-1）免疫治疗的效果。
本研究通过将靶向MES-MDM与TMZ或PD-1抗体治疗相结合为MES亚型GBM患者提供了一种潜在的治疗策略。
