Du Mingjun, Zheng Jianan, Zhou Guangyao, Zhuang Yu, Huang Chenjun, Ye Wei
Department of Thoracic Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 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 Oct 30;16:1696360. doi: 10.3389/fimmu.2025.1696360. eCollection 2025.
Cholesterol metabolism has been shown to affect the tumor microenvironment in various cancers, but its immunological role in lung adenocarcinoma (LUAD) remains unclear.
We integrated 1,682 LUAD samples (including 7 treatment-naïve bulk cohorts and 3 immunotherapy bulk cohorts) to develop a Cholesterol Metabolism Signature (CMS) based on cholesterol metabolism-associated genes. Survival analysis, ROC curves, and PCA were used to evaluate the ability of CMS to predict prognosis and immunotherapy efficacy. Immune infiltration analysis, single-cell transcriptomics, as well as and experiments were further performed to investigate the function and mechanism of the key CMS gene, DHCR7.
CMS effectively predicted the survival outcomes and immunotherapy benefits of LUAD patients, which was consistently validated in all independent cohorts. Patients with high CMS had worse prognosis. Compared with 51 previously published LUAD signatures, CMS showed higher predictive accuracy and stratification ability. Immune-related analyses showed that the high CMS group had reduced immune cell infiltration and suppressed immune function, which was further supported by single-cell analysis revealing enhanced immunosuppressive pathways. Expression of the key gene DHCR7 was highly correlated with CMS score (R = 0.42, P<0.05), negatively associated with many immune-related genes and immune cycles, and promoted poor prognosis and cancer pathways. Multiplex immunohistochemistry confirmed that regions with high DHCR7 expression had fewer infiltrating CD8T and CD20B cells. experiments demonstrated that silencing DHCR7 inhibited the proliferation, invasion, and migration of LUAD cells; mouse models confirmed that suppressing DHCR7 enhanced the efficacy of PD-1 inhibitors. Flow cytometry showed that DHCR7 knockdown significantly increased IFN-γ+CD8T and GZMB+CD8T cell infiltration.
Our study demonstrates that the CMS can effectively predict prognosis and immunotherapy response in LUAD. DHCR7, as a key gene in CMS, is closely related to immune suppression and poor prognosis. Inhibition of DHCR7 can improve the tumor immune microenvironment and enhance the efficacy of immunotherapy, suggesting that DHCR7 is a potential new target for LUAD immunotherapy.
胆固醇代谢已被证明会影响多种癌症的肿瘤微环境，但其在肺腺癌（LUAD）中的免疫作用仍不清楚。
我们整合了1682例LUAD样本（包括7个未经治疗的大量样本队列和3个免疫治疗大量样本队列），以基于胆固醇代谢相关基因开发胆固醇代谢特征（CMS）。采用生存分析、ROC曲线和主成分分析来评估CMS预测预后和免疫治疗疗效的能力。进一步进行免疫浸润分析、单细胞转录组学以及实验，以研究关键CMS基因DHCR7的功能和机制。
CMS有效地预测了LUAD患者的生存结果和免疫治疗获益，这在所有独立队列中均得到一致验证。CMS高的患者预后较差。与之前发表的51种LUAD特征相比，CMS显示出更高的预测准确性和分层能力。免疫相关分析表明，CMS高的组免疫细胞浸润减少且免疫功能受到抑制，单细胞分析显示免疫抑制途径增强进一步支持了这一点。关键基因DHCR7的表达与CMS评分高度相关（R = 0.42，P<0.05），与许多免疫相关基因和免疫周期呈负相关，并促进不良预后和癌症途径发展。多重免疫组化证实，DHCR7高表达区域浸润的CD8T和CD20B细胞较少。实验表明，沉默DHCR7可抑制LUAD细胞的增殖、侵袭和迁移；小鼠模型证实，抑制DHCR7可增强PD-1抑制剂的疗效。流式细胞术显示，敲低DHCR7显著增加了IFN-γ+CD8T和GZMB+CD8T细胞浸润。
我们的研究表明，CMS可以有效地预测LUAD的预后和免疫治疗反应。DHCR7作为CMS中的关键基因，与免疫抑制和不良预后密切相关。抑制DHCR7可以改善肿瘤免疫微环境并增强免疫治疗疗效，这表明DHCR7是LUAD免疫治疗的潜在新靶点。
