<p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a 5-year survival rate of only 12%, driven by late diagnosis, rapid metastasis, and an immunosuppressive tumor microenvironment (TME). Current therapies, including chemotherapy and immune checkpoint blockade, show limited efficacy due to the “cold” TME. Interleukin-1α (IL-1α) plays a central role in PDAC progression. TCGA (<i>n</i> = 178) and ICGC (<i>n</i> = 267) analyses reveal that high IL1A expression independently predicts poor overall survival (HR = 1.99, 95% CI 1.01–3.93) and progression-free survival (HR = 3.11, 95% CI 1.24–7.80). As a biomarker, IL-1α outperforms traditional CA19-9 for risk stratification and treatment selection. Its detection in serum and exosomes supports potential applications in liquid biopsy for early detection. Therapeutically, IL-1α blockers using agents such as anakinra, canakinumab, and nadunolimab show synergy with immune checkpoint inhibitors and chemotherapy. This combination has been evaluated in preclinical models and early-phase clinical trials. It achieves disease control rates of up to 62% and median progression-free survival of up to 6.8&#xa0;months, while also reducing fibrosis and enhancing antitumor immunity. This review synthesizes the critical role of interleukin-1α (IL-1α) in PDAC pathogenesis and its potential implications for immunotherapy and molecular biomarker development. IL-1α is highly expressed in PDAC tumor cells and tumor-associated macrophages (TAMs). It activates the NF-κB and MAPK pathways, thereby promoting epithelial-mesenchymal transition (EMT), stromal fibrosis, and immunosuppression. This includes the recruitment of neutrophils and myeloid-derived suppressor cells (MDSCs), which collectively maintain an immunosuppressive ('cold') tumor microenvironment (TME) and contribute to therapeutic resistance. Future multi-omics stratification, targeted delivery systems, and rational combination strategies hold promise for improving PDAC outcomes.</p>