Abstract B124: Targeting the tumor microenvironment: A novel therapeutic strategy for pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, characterized by extensive desmoplasia, aggressive metastasis, and profound therapeutic resistance driven by its tumor microenvironment (TME). Increasing evidence suggests that cancer–stromal interactions, particularly those involving cancer-associated fibroblasts (CAFs), play critical roles in promoting tumor progression and immune evasion through Activin A signaling. In parallel, aberrant N-glycosylation has emerged as an important regulator of PDAC malignancy and tumor–stroma communication. In our previous study, we identified ACK900, a selective Golgi α-mannosidase II inhibitor with improved specificity and potent anti-metastatic activity. ACK900 suppresses PDAC progression by targeting glycan-dependent mechanisms within the tumor microenvironment. Mechanistically, ACK900 inhibits complex-type N-glycan formation on ATP1B1, a key mediator of cancer–fibroblast interactions that activate Activin A signaling. Furthermore, ACK900 destabilizes the Activin A receptor ALK4 in CAFs while exhibiting selective effects over normal fibroblasts, suggesting its potential to selectively reprogram the stromal compartment. By disrupting tumor–stroma communication and remodeling the tumor microenvironment, ACK900 effectively reduces cancer cell migration, invasion, and metastatic colonization. These findings highlight therapeutic N-glycan modulation as a promising tumor microenvironment–targeted strategy for PDAC treatment.