KRAS-driven cytokine–metabolic crosstalk shapes immune exclusion in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains refractory to immunotherapy, frequently characterized by an immune-excluded tumor microenvironment (TME). Oncogenic KRAS mutation, the predominant genetic driver in PDAC, serves as a master upstream regulator linking tumor-intrinsic signaling with microenvironmental remodeling. Through reshaping cytokine secretion and metabolic programs, mutant KRAS coordinates inflammatory and metabolic networks within the TME. Specifically, KRAS-linked cytokine networks, including tumor-cell-intrinsic mediators such as GM-CSF and microenvironment-associated inflammatory signals involving CXCLs, IL-6, TGF-β, and IL-1β, interact reciprocally with metabolic alterations, such as glycolytic activation, lactate accumulation, hypoxia adaptation, adenosine signaling, and altered amino acid and lipid metabolism. These pathways converge on shared regulatory nodes, notably STAT3, NF-κB, HIF-1α, and MYC, to drive immunosuppressive myeloid cell accumulation, stromal cell activation, extracellular matrix deposition, and restricted CD8+ T-cell infiltration. Furthermore, lactate, adenosine, and physical stromal barriers reinforce these immunosuppressive cascades, thereby establishing spatial immune exclusion. This review summarizes recent evidence on KRAS-driven cytokine–metabolic crosstalk in PDAC and discusses how this genotype-associated regulatory pattern governs immune exclusion, offering novel insights into overcoming immunotherapy resistance.