Background <p>Pancreatic cancer stands among the most aggressive and fatal malignancies, with a steadily increasing incidence worldwide. Its clinical significance lies not only in its high mortality rate but also in the challenges associated with its early detection, limited therapeutic efficacy, and substantial impact on healthcare systems. The asymptomatic nature of the disease in its initial stages, combined with the absence of reliable early biomarkers, contributes to frequent late-stage diagnoses, significantly compromising treatment success and patient survival. Furthermore, the biological complexity of pancreatic tumors – often marked by specific genetic mutations and a highly immunosuppressive tumor microenvironment – drives resistance to conventional therapies, exacerbating clinical management difficulties.</p> Main body <p>This narrative review offers a comprehensive synthesis of the major therapeutic challenges and recent advances in pancreatic cancer management over the past fifteen years. The main challenges include delayed diagnosis, the presence of treatment-resistant tumor subtypes, and the considerable financial burden of care. Particular attention is given to the tumor microenvironment, which impedes drug delivery and immune system activation due to its dense fibrotic stroma and immunosuppressive cellular composition. The review also explores emerging therapeutic strategies, including combination chemotherapy regimens such as folinic acid, fluorouracil, irinotecan, and oxaliplatin, and advanced radiotherapy techniques that aim to enhance precision while minimizing tissue damage. Furthermore, novel immunotherapeutic approaches – including messenger RNA-based vaccines and engineered cellular therapies – show promising results in stimulating targeted immune responses, although they face substantial barriers due to the tumor’s immune evasion mechanisms. Targeted therapies focused on specific genetic alterations, especially those involving KRAS mutations, are also highlighted as potential breakthroughs. The review concludes by emphasizing the relevance of personalized medicine, with biomarker-driven strategies and three-dimensional tumor models offering more tailored and potentially effective interventions.</p> Conclusion <p>Despite meaningful progress in the development of innovative therapeutic modalities, pancreatic cancer continues to present profound medical and scientific challenges. Integrating personalized, interdisciplinary approaches and advancing early diagnostic tools remain essential steps toward improving clinical outcomes and extending survival in affected patients. This review underscores the urgent need for continued research to transform current insights into effective and accessible treatment strategies.</p>