南京医科大学汪秀星团队的最新研究探明了抑制巨噬细胞来源的乳酸转运恢复cGAS-STING信号并增强胶质母细胞瘤的抗肿瘤免疫。2026年1月6日出版的《自然—细胞生物学》杂志发表了这项成果。

在这里，研究人员发现乳酸通过MCT4-MCT1从TAMs转运到GSCs。TAMs为GSC提供乳酸，促进GSC增殖，诱导非同源末端赖氨酸317处连接蛋白KU70 （K317）的乳酸化，从而抑制cGAS-STING信号传导并重塑免疫抑制的TME。抑制乳酸转运或靶向KU70的乳酸化，结合免疫检查点阻断，在免疫活性异种移植模型中显示出附加的治疗效果。这项研究揭示了TAM衍生的乳酸和乳酸化是GSCs中加强免疫抑制微环境的关键调节因子，为开发GBM的联合治疗开辟了道路。

据介绍，胶质母细胞瘤（GBM）是一种复杂的肿瘤微环境（TME）的恶性肿瘤，由GBM干细胞（GSCs）主导，并被肿瘤相关巨噬细胞（TAMs）浸润，并表现出异常的代谢途径。乳酸是促进肿瘤进展的关键糖酵解代谢物；然而，乳酸转运和乳酸化在GBM TME中的机制仍不清楚。

附：英文原文

Title: Inhibiting macrophage-derived lactate transport restores cGAS–STING signalling and enhances antitumour immunity in glioblastoma

Author: Li, Daqi, Cui, Gaoyuan, Yang, Kailin, Lu, Chenfei, Jiang, Yuhan, Zhang, Le, Wu, Qiulian, Dixit, Deobrat, Zhu, Zhe, Gimple, Ryan C., Gu, Danling, Gao, Jiancheng, Lin, Qiankun, Yu, Hang, Shi, Zhumei, Chen, Yun, Wang, Qianghu, Jin, Guangfu, Lin, Fan, Shao, Junfei, Zhou, Qigang, Liu, Chong, Li, Chaojun, You, Yongping, Zhang, Nu, Zhang, Junxia, Qian, Xu, Zhang, Qian, Rich, Jeremy N., Wang, Xiuxing

Issue&Volume: 2026-01-06

Abstract: Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4–MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS–STING signalling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM.

DOI: 10.1038/s41556-025-01839-y

Source: https://www.nature.com/articles/s41556-025-01839-y