代谢免疫调节亚型揭示了多原发性肺癌的预后和治疗见解
Metabolic-immunoregulatory subtypes reveal prognostic and therapeutic insights in multiple primary lung cancer.
摘要(中文译文)
多原发肺癌（MPLC）是一种日益被认识的亚型，其特征为具有独立起源的 distinct 病灶。尽管近期研究已对MPLC的免疫景观进行了分析，但其肿瘤内在代谢特征及免疫调节相互作用仍 largely 未被探索。本研究对来自11例单原发肺癌（SPLC）肿瘤和4例MPLC患者8个样本的单细胞RNA测序数据进行了降维、聚类和细胞类型注释分析。通过通路富集和细胞间相互作用分析，研究了亚型特异性代谢特征和细胞间通讯模式。采用Lasso-Cox回归构建预后模型。使用反卷积算法和免疫相关特征评估免疫微环境特征。进行药物敏感性预测和功能实验以探索潜在治疗意义。本研究鉴定出MPLC肿瘤中富集的代谢上独特的恶性上皮亚群，其特征为氨基酸代谢通路上调以及与免疫抑制性CD4 Treg细胞和肥大细胞之间活跃的MHC-II介导的相互作用。开发了一个基于代谢的八基因预后模型，并在独立的肺腺癌队列中进行了验证，有效区分了患者生存结局。高风险患者表现出免疫抑制性肿瘤微环境特征、免疫治疗应答潜力降低以及独特的药物敏感性谱。功能实验证实，关键代谢基因精胺氧化酶（SMOX）和精胺合酶（SMS）促进肿瘤增殖和侵袭，并伴随PI3K/mTOR通路组分的转录变化，突显了它们在不良预后和治疗脆弱性中的潜在作用。本研究系统表征了MPLC中的恶性亚群，强调了导致不良预后的代谢重编程和免疫调节特征。这些发现为基于代谢的预后分层提供了依据，并突显了改善临床结局的潜在治疗策略。
Abstract
Multiple primary lung cancer (MPLC) is an increasingly recognized subtype characterized by distinct lesions with independent origins. While recent studies have profiled the immune landscape of MPLC, its tumor-intrinsic metabolic features and immunoregulatory interactions remain largely unexplored. Single-cell RNA sequencing data from 11 single primary lung cancer (SPLC) tumors and 8 samples from 4 MPLC patients were analyzed using dimensionality reduction, clustering, and cell type annotation. Subtype-specific metabolic features and intercellular communication patterns were investigated through pathway enrichment and cell-cell interaction analyses. A prognostic model was constructed using Lasso-Cox regression. Immune microenvironment characteristics were assessed using deconvolution algorithms and immune-related signatures. Drug sensitivity prediction and functional assays were performed to explore potential therapeutic implications. This study identified a metabolically distinct malignant epithelial subpopulation enriched in MPLC tumors, characterized by upregulation of amino acid metabolism pathways and active MHC-II-mediated interactions with immunosuppressive CD4 Treg cells and mast cells. A metabolism-based eight-gene prognostic model was developed and validated in independent lung adenocarcinoma cohorts, effectively stratifying patient survival outcomes. High-risk patients exhibited immunosuppressive tumor microenvironment features, reduced immunotherapy response potential, and distinct drug sensitivity profiles. Functional assays confirmed that key metabolic genes, spermine oxidase (SMOX) and spermine synthase (SMS), promoted tumor proliferation and invasion, accompanied by transcriptional changes in PI3K/mTOR pathway components, highlighting their potential roles in poor prognosis and therapeutic vulnerability. This study provides a systematic characterization of malignant subpopulations in MPLC, highlighting metabolic reprogramming and immunoregulatory features that contribute to poor prognosis. These findings provide a rationale for metabolism-based prognostic stratification and highlight potential therapeutic strategies to improve clinical outcomes.
如何引用
AMA
Yuli Zhao, Hanyu Zhao, Hui Wu, Huimin Tao, Chunmin Yang. Metabolic-immunoregulatory subtypes reveal prognostic and therapeutic insights in multiple primary lung cancer.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1827965.
APA
Yuli Zhao, Hanyu Zhao, Hui Wu, Huimin Tao, Chunmin Yang (2026). Metabolic-immunoregulatory subtypes reveal prognostic and therapeutic insights in multiple primary lung cancer.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1827965
GB/T 7714
Yuli Zhao, Hanyu Zhao, Hui Wu, Huimin Tao, Chunmin Yang. Metabolic-immunoregulatory subtypes reveal prognostic and therapeutic insights in multiple primary lung cancer.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1827965.
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