Innate immunity-stroma crosstalk in pancreatic cancer: overcoming spatial and metabolic barriers to immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound resistance to current immunotherapies, a challenge largely attributed to its uniquely immunosuppressive and desmoplastic tumor microenvironment (TME). At the heart of this therapeutic recalcitrance lies the dynamic, bidirectional crosstalk between innate immune cells—particularly tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs)—and stromal components, notably cancer-associated fibroblasts (CAFs). This review comprehensively delineates how the innate immunity-stroma axis establishes formidable spatial and metabolic barriers that thwart effective antitumor immunity. Spatially, dense collagen matrices, periductal fibroblast organization, and neutrophil extracellular traps (NETs) create physical checkpoints that exclude cytotoxic CD8+ T cells and natural killer (NK) cells from tumor nests. Metabolically, elevated lactate, cholesterol dysregulation, adenosine accumulation, and altered polyamine metabolism synergistically paralyze effector lymphocytes while driving immunosuppressive myeloid polarization. We highlight the key molecular networks orchestrating this pathological crosstalk, including the NF-κB, IL-1β, JAK/STAT3, and TGF-β signaling pathways. Furthermore, we summarize emerging therapeutic strategies designed to dismantle these barriers, encompassing macrophage reprogramming, CAF modulation, and metabolic interventions. Finally, we discuss the multidimensional “3D+R” framework—integrating de-desmoplasia, de-adenosine, de-novo antigen presentation, and rational sequencing—as a conceptual roadmap for rationally designed combination therapies to overcome PDAC immunotherapy resistance.