Table 6_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）以重度免疫抑制性肿瘤微环境（Tumor Microenvironment, TME）为核心特征，该微环境会限制免疫治疗的临床疗效。新兴研究证据表明，肿瘤特异性代谢重编程可能驱动PAAD的疾病进展，并塑造其免疫微环境格局。

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，以识别影响免疫细胞浸润、肿瘤进展及患者生存期的关键代谢相关基因（Metabolism-Related Genes, MRGs）。基于包含ANLN、PKMYT1与HMGA1在内的9个关键MRGs，本研究开发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风险组所关联的代谢通路。此外，本研究开展了体外实验与药物敏感性分析，以验证所选MRGs的致癌作用，并探讨其潜在治疗价值。

结果
MPI可有效将患者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TME显著相关，具体表现为CD8+ T细胞浸润减少及免疫检查点（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组则以脂肪酸代谢为主导。实验验证证实，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可显著降低肿瘤细胞的糖酵解活性、迁移能力与免疫逃逸能力。药物敏感性分析结果显示，高MPI患者对吉西他滨存在耐药性，但对阿法替尼敏感。尽管TIDE（Tumor Immune Dysfunction and Exclusion, TIDE）分析预测高MPI肿瘤对免疫检查点抑制剂（Immune Checkpoint Inhibitor, ICI）存在耐药性，但仍有部分患者可从抗PD-L1治疗中获得良好应答。

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TME并影响治疗结局提供了全面的分析框架。通过精准的患者分层，MPI可作为指导临床治疗决策的可靠工具，包括靶向治疗方案选择及免疫治疗疗效预测，最终为PAAD的个体化管理提供了新的潜在可能。