Li Chenchen, Lin Yi, Zheng Haoran, Zeng Hengda, Xu Longhao, Wu Daqin, Lao Jianwen, Cai Peicong, Liang Shuai, Wang Chunhui, Lin Tianxin, Zhong Wenlong
Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
Cancer Immunol Immunother. 2025 Jun 7;74(8):240. doi: 10.1007/s00262-025-04074-4.
Resistance to immune checkpoint inhibitors remains a significant challenge in the treatment of cancer. Emerging evidence suggests that metabolic reprogramming plays a crucial role in tumor metabolism and progression. Our study strived to investigate the role and underlying mechanisms of the glutamate transporter SLC1A6 in resistance to immunotherapy of cancer.
Single-cell RNA sequencing was performed on bladder cancer patients receiving neoadjuvant immunotherapy to identify the expression of SLC1A6 in treatment-resistant cases. The clinical prognostic value of SLC1A6 in cancer was validated using publicly available lung cancer single-cell datasets, as well as transcriptomic data from both bladder and lung cancer cohorts. Flow cytometry was employed to assess the impact of SLC1A6 knockdown on the effector function of CD8⁺ T cell. In vivo tumor models were used to evaluate the role of SLC1A6 in immunotherapy resistance, with immunofluorescence staining performed to examine GZMB⁺ CD8⁺ T cell infiltration.
SLC1A6 was highly expressed in bladder cancer patients resistant to neoadjuvant immunotherapy, and its expression was associated with disease progression, poor prognosis, and low immune infiltration. Knockdown of SLC1A6 in tumor cells enhanced CD8⁺ T cell effector function. SLC1A6 knockdown also improved the efficacy of immunotherapy and increased the infiltration of GZMB⁺ CD8⁺ T cells within the tumor microenvironment.
SLC1A6 plays a critical role in resistance to immunotherapy in cancer. Targeting SLC1A6 may provide a promising therapeutic strategy for improving responses to neoadjuvant immunotherapy and advancing combination treatment approaches.
对免疫检查点抑制剂的耐药性仍然是癌症治疗中的一项重大挑战。新出现的证据表明，代谢重编程在肿瘤代谢和进展中起着关键作用。我们的研究旨在探讨谷氨酸转运体SLC1A6在癌症免疫治疗耐药中的作用及潜在机制。
对接受新辅助免疫治疗的膀胱癌患者进行单细胞RNA测序，以确定SLC1A6在治疗耐药病例中的表达。利用公开可用的肺癌单细胞数据集以及膀胱癌和肺癌队列的转录组数据，验证了SLC1A6在癌症中的临床预后价值。采用流式细胞术评估SLC1A6敲低对CD8⁺T细胞效应功能的影响。利用体内肿瘤模型评估SLC1A6在免疫治疗耐药中的作用，并进行免疫荧光染色以检测GZMB⁺CD8⁺T细胞浸润情况。
SLC1A6在对新辅助免疫治疗耐药的膀胱癌患者中高表达，其表达与疾病进展、预后不良和低免疫浸润相关。肿瘤细胞中SLC1A6的敲低增强了CD8⁺T细胞的效应功能。SLC1A6敲低还提高了免疫治疗的疗效，并增加了肿瘤微环境中GZMB⁺CD8⁺T细胞的浸润。
SLC1A6在癌症免疫治疗耐药中起关键作用。靶向SLC1A6可能为改善对新辅助免疫治疗的反应和推进联合治疗方法提供一种有前景的治疗策略。
