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<p>Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Despite advancements in treatment, prognosis for patients with advanced stages remains poor. Metabolic reprogramming in the tumor microenvironment, particularly abnormal glycolysis, plays a crucial role in immune evasion and treatment response. We collected nine single-cell datasets to create a single-cell atlas of CD8 + T cells from 89 NSCLC patients, revealing ten distinct states of these cells. We employed a multimodal data analysis approach, integrating bulk transcriptomics, single-cell transcriptomics, spatial transcriptomics, and proteomics. Using 117 machine learning models, we identified key genes associated with NSCLC metastasis. Notably, the StepCox[forward] + Lasso model was instrumental in pinpointing key genes that significantly impact disease prognosis. Our analysis revealed that LTB + LDHA + CD8 + T cells have a distinct metabolic and immune phenotype, characterized by enhanced glycolysis and elevated lactate production. This not only facilitates tumor cell migration and invasion but also impairs the cytotoxic function of CD8 + T cells. Furthermore, our machine learning models identified four key genes significantly associated with NSCLC metastasis: <i>TBCD</i>, <i>PTPRC</i>, <i>LDHA</i>, and <i>ACTR2</i>. Of these, high <i>LDHA</i> expression was strongly linked to poorer responses to immunotherapy and a higher risk of therapy resistance. LTB + LDHA + CD8 + T cells also reduced antitumor immune responses by inhibiting the secretion of effector molecules like <i>GNLY</i>. Additionally, elevated <i>LDHA</i> expression was associated with reduced CD8 + T cell infiltration, which further promotes tumor immune evasion. This study highlights the heterogeneity of CD8 + T cells in NSCLC, emphasizing the unique role of the LTB + CD8 + Tn subpopulation in metastasis. <i>LDHA</i> is identified as a critical key gene with a significant impact on immunotherapy outcomes, presenting a potential therapeutic target. These insights offer new biomarkers and targeted strategies for personalized immune therapy.</p>

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Metabolic alterations driven by LDHA in CD8 + T cells promote immune evasion and therapy resistance in NSCLC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月8日

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  • Hao Wen,
  • Panpan Zhang,
  • Juan Zhao,
  • Yakui Liu,
  • Lei Wan,
  • Haoran Li,
  • Jun Yi,
  • Xinqiang Li

摘要

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Despite advancements in treatment, prognosis for patients with advanced stages remains poor. Metabolic reprogramming in the tumor microenvironment, particularly abnormal glycolysis, plays a crucial role in immune evasion and treatment response. We collected nine single-cell datasets to create a single-cell atlas of CD8 + T cells from 89 NSCLC patients, revealing ten distinct states of these cells. We employed a multimodal data analysis approach, integrating bulk transcriptomics, single-cell transcriptomics, spatial transcriptomics, and proteomics. Using 117 machine learning models, we identified key genes associated with NSCLC metastasis. Notably, the StepCox[forward] + Lasso model was instrumental in pinpointing key genes that significantly impact disease prognosis. Our analysis revealed that LTB + LDHA + CD8 + T cells have a distinct metabolic and immune phenotype, characterized by enhanced glycolysis and elevated lactate production. This not only facilitates tumor cell migration and invasion but also impairs the cytotoxic function of CD8 + T cells. Furthermore, our machine learning models identified four key genes significantly associated with NSCLC metastasis: TBCD, PTPRC, LDHA, and ACTR2. Of these, high LDHA expression was strongly linked to poorer responses to immunotherapy and a higher risk of therapy resistance. LTB + LDHA + CD8 + T cells also reduced antitumor immune responses by inhibiting the secretion of effector molecules like GNLY. Additionally, elevated LDHA expression was associated with reduced CD8 + T cell infiltration, which further promotes tumor immune evasion. This study highlights the heterogeneity of CD8 + T cells in NSCLC, emphasizing the unique role of the LTB + CD8 + Tn subpopulation in metastasis. LDHA is identified as a critical key gene with a significant impact on immunotherapy outcomes, presenting a potential therapeutic target. These insights offer new biomarkers and targeted strategies for personalized immune therapy.