Metabolic Reprogramming Shapes the Immune Microenvironment in Pancreatic Adenocarcinoma: Prognostic Implications and Therapeutic Targets

Weihua Song ¹ Yabin Yu ² Siqi Wang ¹ Zhengyi Cui ³ Qiusi Zhu ⁴ Wangrui Liu ^1* Shiyin Wei ⁵ Jiachang Chi ¹

• ¹ Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
• ² Department of Hepatobiliary and Pancreatic Surgery, Huai'an First People's Hospital, Huai’an, Jiangsu Province, China
• ³ Texas Health and Science University, Austin, Texas, United States
• ⁴ Northeast Agricultural University, Harbin, Heilongjiang Province, China
• ⁵ Youjiang Medical University for Nationalities, Baise, Guangx, China

Pancreatic adenocarcinoma (PAAD) is a highly aggressive malignancy with a profoundly immunosuppressive tumor microenvironment (TME), characterized by limited response to immunotherapy. This study investigates the role of tumor-specific metabolic reprogramming in shaping the immune landscape of PAAD and its implications for prognosis and therapeutic strategies. By integrating multi-omics data from TCGA, GEO, and ICGC, we identified key metabolism-related genes (MRGs) that influence immune cell infiltration, tumor progression, and patient survival.We developed a novel metabolic-prognostic index (MPI) based on nine key MRGs, including ANLN, PKMYT1, and HMGA1, which effectively stratifies patients into high-and low-risk groups. MPI was constructed and validated as a robust prognostic tool. High MPI scores were associated with poor overall survival, increased tumor mutation burden (TMB), and an immunosuppressive TME, including reduced infiltration of CD8+ T cells and elevated expression of immune checkpoint markers such as PD-L1 and TGF-β . Functional enrichment analysis revealed glycolysis and folate biosynthesis as dominant pathways in high MPI score groups, while fatty acid metabolism was enriched in low MPI groups.Further experimental validation highlighted the oncogenic role of ANLN, a glycolysis-associated gene, in promoting epithelial-mesenchymal transition (EMT) and immune evasion via the NF-κB signaling pathway. Knockdown of ANLN in vitro significantly suppressed glycolytic activity, tumor cell migration, and immune evasion, thereby confirming its potential as a therapeutic target.Drug sensitivity analysis revealed that high MPI score patients exhibited resistance to chemotherapy agents such as gemcitabine but showed sensitivity to targeted inhibitors like Afatinib. Additionally, while high MPI scores predicted resistance to immune checkpoint inhibitors (ICI) based on TIDE analysis, a subset of high-score patients responded favorably to anti-PD-L1 therapy.This study provides a comprehensive framework for understanding the interplay between metabolic reprogramming and immune modulation in PAAD. By effectively stratifying patients, the MPI score serves as a guide for treatment decisions, particularly in selecting targeted therapies and predicting the efficacy of immunotherapy