TY  - EJOU
AU  - Chen, Mao-Lin 
AU  - Chung, I-Che 
AU  - Huang, Kevin Chih-Yang 
AU  - Chao, K. S. Clifford 
AU  - Yuan, Ta-Tung 

TI  - TGFβ Blockade by Inhibition of Enolase-1-Mediated Plasmin Targets Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma
T2  - Oncology Research

PY  - 
VL  - 
IS  - 
SN  - 1555-3906

AB  - <b>Background:</b> Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive and metabolically rewired tumor microenvironment (TME). Although α-enolase (ENO1) is frequently overexpressed in PDAC and associated with poor prognosis, its functional role in TME remodeling remains unclear. This study investigated the role of ENO1 in plasmin-dependent transforming growth factor β (TGFβ) activation and metabolic adaptation in PDAC and evaluated the therapeutic potential of HuL001, a first-in-class humanized anti-ENO1 monoclonal antibody. <b>Methods:</b> ENO1 expression and clinical relevance were evaluated in PDAC tissues by immunohistochemistry. Mechanistic studies were performed using PDAC-monocyte co-culture systems, reverse transcription-quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), flow cytometry, and cell viability assays. The therapeutic effects of HuL001 were further assessed in multiple PDAC xenograft models. <b>Results:</b> Surface ENO1 expression was elevated in advanced PDAC and was associated with poorer overall survival. HuL001 suppressed monocyte-driven PDAC proliferation and reduced factors associated with M2-like macrophages (alternatively activated macrophages), including <i>TGFB1</i>, <i>IL10</i>, and <i>VEGFA</i>. Mechanistically, HuL001 inhibited ENO1-dependent plasmin-mediated activation of latent TGFβ and attenuated TGFβ-induced ENO1 expression, plasmin activity, hexokinase 2 (HK2) expression, and lactate production. <i>In vivo</i>, HuL001 inhibited PDAC growth and enhanced the antitumor efficacy of gemcitabine in three xenograft models, with greater suppression of tumor growth, intratumoral lactate, and active TGFβ than gemcitabine alone. <b>Conclusion:</b> These findings identify ENO1 as a functional driver of plasmin-dependent TGFβ activation and metabolic adaptation in PDAC and support HuL001 as a promising therapeutic strategy, particularly in combination with gemcitabine.
KW  - ENO1; TGFβ activation; pancreatic ductal adenocarcinoma; monoclonal antibody; tumor microenvironment; tumor-associated macrophage

DO  - 10.32604/or.2026.077930