Ding Yang, Wang Dingli, Yan Dali, Fan Jun, Ding Zongli, Xue Lei
Department of Pathology, Nanjing Drum Tower Hospital Group Suqian Hospital, Suqian, China.
Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Front Immunol. 2025 Apr 16;16:1575084. doi: 10.3389/fimmu.2025.1575084. eCollection 2025.
Lung adenocarcinoma is the most prevalent type of small-cell carcinoma, with a poor prognosis. For advanced-stage patients, the efficacy of immunotherapy is suboptimal. The STING signaling pathway plays a pivotal role in the immunotherapy of lung adenocarcinoma; therefore, further investigation into the relationship between the STING pathway and lung adenocarcinoma is warranted.
We conducted a comprehensive analysis integrating single-cell RNA sequencing (scRNA-seq) data with bulk transcriptomic profiles from public databases (GEO, TCGA). STING pathway-related genes were identified through Genecard database. Advanced bioinformatics analyses using R packages (Seurat, CellChat) revealed transcriptomic heterogeneity, intercellular communication networks, and immune landscape characteristics. We developed a STING pathway-related signature (STINGsig) using 101 machine learning frameworks. The functional significance of ERRFI1, a key component of STINGsig, was validated through mouse models and multicolor flow cytometry, particularly examining its role in enhancing antitumor immunity and potential synergy with α-PD1 therapy.
Our single-cell analysis identified and characterized 15 distinct cell populations, including epithelial cells, macrophages, fibroblasts, T cells, B cells, and endothelial cells, each with unique marker gene profiles. STING pathway activity scoring revealed elevated activation in neutrophils, epithelial cells, B cells, and T cells, contrasting with lower activity in inflammatory macrophages. Cell-cell communication analysis demonstrated enhanced interaction networks in high-STING-score cells, particularly evident in fibroblasts and endothelial cells. The developed STINGsig showed robust prognostic value and revealed distinct immune microenvironment characteristics between risk groups. Notably, ERRFI1 knockdown experiments confirmed its significant role in modulating antitumor immunity and enhancing α-PD1 therapy response.
The STING-related pathway exhibited distinct expression levels across 15 cell populations, with high-score cells showing enhanced tumor-promoting pathways, active immune interactions, and enrichment in fibroblasts and IFI27+ inflammatory macrophages. In contrast, low-score cells were associated with epithelial phenotypes and reduced immune activity. We developed a robust STING pathway-related signature (STINGsig), which identified key prognostic genes and was linked to the immune microenvironment. Through experiments, we confirmed that knockdown of ERRFI1, a critical gene within the STINGsig, significantly enhances antitumor immunity and synergizes with α-PD1 therapy in a lung cancer model, underscoring its therapeutic potential in modulating immune responses.
肺腺癌是最常见的小细胞癌类型，预后较差。对于晚期患者，免疫治疗的疗效欠佳。STING信号通路在肺腺癌的免疫治疗中起关键作用；因此，有必要进一步研究STING通路与肺腺癌之间的关系。
我们进行了一项综合分析，将单细胞RNA测序（scRNA-seq）数据与来自公共数据库（GEO, TCGA）的批量转录组图谱相结合。通过Genecard数据库鉴定STING通路相关基因。使用R包（Seurat, CellChat）进行的高级生物信息学分析揭示了转录组异质性、细胞间通讯网络和免疫景观特征。我们使用101个机器学习框架开发了一个STING通路相关特征（STINGsig）。通过小鼠模型和多色流式细胞术验证了STINGsig的关键组成部分ERRFI1的功能意义，特别研究了其在增强抗肿瘤免疫和与α-PD1治疗潜在协同作用中的作用。
我们的单细胞分析鉴定并表征了15个不同的细胞群，包括上皮细胞、巨噬细胞、成纤维细胞、T细胞、B细胞和内皮细胞，每个细胞群都有独特的标记基因谱。STING通路活性评分显示中性粒细胞、上皮细胞、B细胞和T细胞中的激活升高，与炎症巨噬细胞中的较低活性形成对比。细胞间通讯分析表明，高STING评分细胞中的相互作用网络增强，在成纤维细胞和内皮细胞中尤为明显。所开发的STINGsig显示出强大的预后价值，并揭示了风险组之间不同的免疫微环境特征。值得注意的是，ERRFI1敲低实验证实了其在调节抗肿瘤免疫和增强α-PD1治疗反应中的重要作用。
STING相关通路在15个细胞群中表现出不同的表达水平，高分细胞显示出增强的肿瘤促进通路、活跃的免疫相互作用以及成纤维细胞和IFI27+炎症巨噬细胞的富集。相比之下，低分细胞与上皮表型和免疫活性降低有关。我们开发了一个强大的STING通路相关特征（STINGsig），它确定了关键的预后基因，并与免疫微环境相关。通过实验，我们证实敲低STINGsig中的关键基因ERRFI1可显著增强抗肿瘤免疫，并在肺癌模型中与α-PD1治疗协同作用，突出了其在调节免疫反应中的治疗潜力。
