Table 9_Metabolic reprogramming shapes the immune microenvironment in pancreatic adenocarcinoma: prognostic implications and therapeutic targets.csv

IntroductionPancreatic adenocarcinoma (PAAD) is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that limits the efficacy of immunotherapy. Emerging evidence suggests that tumor-specific metabolic reprogramming may drive disease progression and shape the immune landscape in PAAD.
MethodsWe integrated multi-omics data from TCGA, GEO, and ICGC to identify key metabolism-related genes (MRGs) that influence immune cell infiltration, tumor progression, and patient survival. Based on nine pivotal MRGs (including ANLN, PKMYT1, and HMGA1), we developed and validated a novel metabolic-prognostic index (MPI). Functional enrichment analyses were conducted to elucidate the metabolic pathways associated with different MPI risk groups. In vitro experiments and drug sensitivity analyses were performed to confirm the oncogenic role of selected MRGs and to explore their therapeutic implications.
ResultsThe MPI effectively stratified patients into high- and low-risk groups. High-MPI scores correlated with poor overall survival, elevated tumor mutation burden (TMB), and an immunosuppressive TME, evidenced by reduced CD8⁺ T-cell infiltration and increased expression of immune checkpoints (PD-L1, TGF-β). Functional enrichment revealed glycolysis and folate biosynthesis as dominant pathways in high-MPI groups, whereas fatty acid metabolism prevailed in low-MPI groups. Experimental validation underscored the role of ANLN in promoting epithelial-mesenchymal transition (EMT) and immune evasion via NF-κB signaling. ANLN knockdown significantly reduced glycolytic activity, tumor cell migration, and immune evasion. Drug sensitivity analyses indicated resistance to gemcitabine but sensitivity to afatinib in high-MPI patients. Although TIDE analysis predicted immune checkpoint inhibitor (ICI) resistance in high-MPI tumors, a subset of patients showed favorable responses to anti-PD-L1 therapy.
DiscussionThese findings provide a comprehensive framework for understanding how metabolic reprogramming shapes PAAD’s immunosuppressive TME and affects treatment outcomes. By accurately stratifying patients, the MPI serves as a promising tool to guide therapeutic decisions, including targeted therapy selection and immunotherapy prediction, ultimately offering potential for more personalized management of PAAD.

引言
胰腺腺癌（Pancreatic adenocarcinoma, PAAD）以极度免疫抑制的肿瘤微环境（tumor microenvironment, TME）为特征，该特征限制了免疫治疗的疗效。越来越多的证据表明，肿瘤特异性代谢重编程可能驱动PAAD的疾病进展，并重塑其免疫景观。
方法
本研究整合了来自癌症基因组图谱（The Cancer Genome Atlas, TCGA）、基因表达综合数据库（Gene Expression Omnibus, GEO）以及国际癌症基因组联盟（International Cancer Genome Consortium, ICGC）的多组学数据，以筛选影响免疫细胞浸润、肿瘤进展及患者生存的关键代谢相关基因（metabolism-related genes, MRGs）。基于ANLN、PKMYT1、HMGA1等9个核心代谢相关基因，我们构建并验证了一种新型代谢预后指数（metabolic-prognostic index, MPI）。通过功能富集分析，阐明了不同MPI风险分组所关联的代谢通路。此外，我们开展了体外实验与药物敏感性分析，以验证筛选出的代谢相关基因的致癌作用，并探索其治疗应用价值。
结果
代谢预后指数可有效将患者划分为高风险组与低风险组。高MPI评分与较差的总生存期、升高的肿瘤突变负荷（tumor mutation burden, TMB）以及免疫抑制性肿瘤微环境显著相关，具体表现为CD8+ T细胞浸润减少以及免疫检查点（PD-L1、TGF-β）表达上调。功能富集分析显示，高MPI组以糖酵解与叶酸生物合成为主要代谢通路，而低MPI组则以脂肪酸代谢占主导。实验验证结果证实，ANLN可通过NF-κB信号通路促进上皮间质转化（epithelial-mesenchymal transition, EMT）与免疫逃逸；敲低ANLN可显著降低糖酵解活性、肿瘤细胞迁移能力与免疫逃逸能力。药物敏感性分析表明，高MPI患者对吉西他滨（gemcitabine）产生耐药性，但对阿法替尼（afatinib）敏感。尽管TIDE分析预测高MPI肿瘤存在免疫检查点抑制剂（immune checkpoint inhibitor, ICI）耐药性，但其中部分患者对抗PD-L1治疗表现出良好响应。
讨论
本研究结果为理解代谢重编程如何塑造PAAD的免疫抑制性肿瘤微环境并影响治疗结局提供了全面的分析框架。通过精准划分患者风险分层，代谢预后指数有望成为指导治疗决策的有效工具，包括靶向治疗方案选择与免疫治疗疗效预测，最终为PAAD的个性化管理提供潜在可行的路径。