Yuwei Sun, Wenyang Nie, Zhikai Xiahou, Xiaojing Wang, Wenjia Liu, Zongkai Liu, Zhiheng Lin, Zhaidong Liu
College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
China Institute of Sport and Health Science, Beijing Sport University, Beijing, China.
Front Immunol. 2025 Jul 4;16:1591123. doi: 10.3389/fimmu.2025.1591123. eCollection 2025.
Globally, gastric cancer (GC) stands as the fifth most prevalent form of malignant neoplasm and represents a significant contributor to mortality associated with oncological conditions. Despite advancements in therapeutic strategies for GC, the outcomes for patients with advanced stages of the disease continue to be unfavorable, largely due to tumor heterogeneity and the challenges posed by resistance to therapeutic agents. Metabolic reprogramming is pivotal in driving the advancement of GC, contributing to the development of resistance to pharmacological treatments and facilitating the cancer's ability to evade immune surveillance. Developing multi-target comprehensive treatment strategies by integrating tumor microenvironment (TME) modulation holds promise for significantly improving therapeutic efficacy.
The study analyzed GC and identified key cell subtypes by integrating data derived from single-cell RNA-sequencing (scRNA-seq) alongside spatial transcriptomics information. Cell type identification was accomplished using the tool of Seurat, and the spatial distribution of cell types was revealed through the Robust Cell Type Decomposition technique. CellChat was used to analyze the interactions between key cell subtypes and other cells, and the "StLearn" package was employed to investigate spatial cell communication in depth. Additionally, the functional role of the key molecule ELK4 was validated through experiments.
This research utilized scRNA-seq combined with spatial transcriptomics to comprehensively analyze GC, identifying the C1 + subtype, which exhibited high proliferative activity, metabolic reprogramming capabilities, and immune evasion properties. It was found that the C1 + subtype closely interacted with fibroblasts and pericytes via the PARs signaling pathway. Additionally, experiments confirmed that knockdown of ELK4 substantially curbed tumor cell proliferation, migration, and invasion.
This study revealed the main significance of the C1 + subtype in GC, elucidating its core mechanisms in tumor progression, metabolic reprogramming, and immune evasion. ELK4 was identified as a key regulatory factor that markedly enhanced the proliferation, migratory capacity, and invasive potential of tumor cells, while changes in the TME were a driving force behind immune suppression and drug resistance. The findings underscored the importance of developing specific therapeutic targets, targeting metabolic reprogramming, and overcoming immune evasion, providing new theoretical foundations.
在全球范围内，胃癌（GC）是第五大最常见的恶性肿瘤形式，是肿瘤相关死亡的重要原因。尽管胃癌治疗策略取得了进展，但晚期患者的治疗结果仍然不理想，这主要是由于肿瘤异质性以及对治疗药物产生耐药性所带来的挑战。代谢重编程在推动胃癌进展中起着关键作用，导致对药物治疗产生耐药性，并促进癌症逃避免疫监视的能力。通过整合肿瘤微环境（TME）调节来制定多靶点综合治疗策略有望显著提高治疗效果。
该研究通过整合来自单细胞RNA测序（scRNA-seq）的数据以及空间转录组学信息，对胃癌进行分析并确定关键细胞亚型。使用Seurat工具完成细胞类型鉴定，并通过稳健细胞类型分解技术揭示细胞类型的空间分布。使用CellChat分析关键细胞亚型与其他细胞之间的相互作用，并使用“StLearn”软件包深入研究空间细胞通讯。此外，通过实验验证了关键分子ELK4的功能作用。
本研究利用scRNA-seq结合空间转录组学对胃癌进行全面分析，确定了C1+亚型，该亚型表现出高增殖活性、代谢重编程能力和免疫逃避特性。发现C1+亚型通过PARs信号通路与成纤维细胞和周细胞密切相互作用。此外，实验证实敲低ELK4可显著抑制肿瘤细胞的增殖、迁移和侵袭。
本研究揭示了C1+亚型在胃癌中的主要意义，阐明了其在肿瘤进展、代谢重编程和免疫逃避中的核心机制。ELK4被确定为一个关键调节因子，它显著增强了肿瘤细胞的增殖、迁移能力和侵袭潜力，而TME的变化是免疫抑制和耐药性的驱动力。这些发现强调了开发特定治疗靶点、针对代谢重编程和克服免疫逃避的重要性，提供了新的理论基础。
