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<p>Sarcomas are aggressive, immunologically cold tumors with limited benefit from immune-checkpoint blockade (ICB). Through integrated multi-omics, functional, and clinical analyses, we identify pyruvate dehydrogenase alpha 1 (PDHA1)—a cuproptosis-linked metabolic gene—as a driver of sarcoma progression and immune evasion. PDHA1 is consistently overexpressed across TCGA/GEO/ICGC cohorts and associates with poor prognosis, stromal activation, and reduced immune scores; single-cell RNA-seq of the immune compartment shows PDHA1 expression across multiple immune populations, with higher levels in T cells and monocytes/dendritic cells. PDHA1 knockdown diminishes proliferation, invasion, clonogenicity, and PD-L1 levels while increasing apoptosis. Mechanistically, PDHA1 elevates E2F1, which binds and transactivates the PD-L1 promoter; rescue assays confirm E2F1-dependent PD-L1 induction. Copper chelation with tetrathiomolybdate lowers lipoylated DLAT and suppresses the PDHA1–E2F1–PD-L1 axis. In 3D spheroids, xenografts, and multiplex immunofluorescence, high PDHA1 aligns with larger tumors, higher Ki-67/BCL-2, lower cleaved caspase-3, increased PD-L1, and reduced CD8⁺ T-cell infiltration. PDHA1 hypomethylation correlates with worse survival. PDHA1 status also modulates sensitivity to phenformin and the E2F1 pathway inhibitor NSC-207895. Collectively, PDHA1 orchestrates a cuproptosis-associated E2F1–PD-L1 program that promotes immune exclusion yet predicts ICB responsiveness, supporting PDHA1 as a clinically actionable biomarker and metabolic–immunologic target in sarcoma.</p>

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Cuproptosis-associated PDHA1 promotes sarcoma progression and immunotherapy responsiveness via the E2F1–PD-L1 axis: a multi-omics and clinical validation study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Haotian Qin,
  • Tiantian Qi,
  • Nan Yao,
  • Weibei Sheng,
  • Jinhao Deng,
  • Junyu Qian,
  • Deli Wang,
  • Hui Zeng,
  • Jian Weng,
  • Jun Yang,
  • Fei Yu

摘要

Sarcomas are aggressive, immunologically cold tumors with limited benefit from immune-checkpoint blockade (ICB). Through integrated multi-omics, functional, and clinical analyses, we identify pyruvate dehydrogenase alpha 1 (PDHA1)—a cuproptosis-linked metabolic gene—as a driver of sarcoma progression and immune evasion. PDHA1 is consistently overexpressed across TCGA/GEO/ICGC cohorts and associates with poor prognosis, stromal activation, and reduced immune scores; single-cell RNA-seq of the immune compartment shows PDHA1 expression across multiple immune populations, with higher levels in T cells and monocytes/dendritic cells. PDHA1 knockdown diminishes proliferation, invasion, clonogenicity, and PD-L1 levels while increasing apoptosis. Mechanistically, PDHA1 elevates E2F1, which binds and transactivates the PD-L1 promoter; rescue assays confirm E2F1-dependent PD-L1 induction. Copper chelation with tetrathiomolybdate lowers lipoylated DLAT and suppresses the PDHA1–E2F1–PD-L1 axis. In 3D spheroids, xenografts, and multiplex immunofluorescence, high PDHA1 aligns with larger tumors, higher Ki-67/BCL-2, lower cleaved caspase-3, increased PD-L1, and reduced CD8⁺ T-cell infiltration. PDHA1 hypomethylation correlates with worse survival. PDHA1 status also modulates sensitivity to phenformin and the E2F1 pathway inhibitor NSC-207895. Collectively, PDHA1 orchestrates a cuproptosis-associated E2F1–PD-L1 program that promotes immune exclusion yet predicts ICB responsiveness, supporting PDHA1 as a clinically actionable biomarker and metabolic–immunologic target in sarcoma.