RAS signaling and remodeling of the immune microenvironment in pancreatic ductal adenocarcinoma: implications of emerging RAS-targeted therapy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Its poor prognosis is closely related to early invasion, extensive stromal deposition, and a strongly immunosuppressive tumor microenvironment. Mutant KRAS is a major driver of PDAC initiation and progression, but its effects are not limited to cancer-cell proliferation. Increasing evidence indicates that oncogenic RAS signaling also alters the surrounding microenvironment by affecting fibroblast activation, extracellular matrix production, antigen presentation, myeloid-cell infiltration, and inflammatory cytokine signaling. These changes can restrict antitumor immune responses and may contribute to treatment resistance. As direct RAS-targeted agents move into clinical development, their effects on tumor immunity have become increasingly relevant. By integrating RAS-driven stromal and immune remodeling with emerging allele-specific and multi-selective RAS therapies, this Mini Review bridges mechanistic and clinical perspectives that are often discussed separately. This framework highlights the rationale for combining RAS inhibitors with immunotherapy and other microenvironment-targeted treatments.