The mechanisms and clinical prospects of combining chemotherapy with immunotherapy for advanced pancreatic cancer.

Advanced pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors, with a five-year survival rate below 9%. Its profound resistance to treatment is driven by a uniquely immunosuppressive and fibrotic tumor microenvironment (TME), which has rendered single-agent immunotherapy largely ineffective. This review critically analyzes the biological rationale, clinical outcomes, and evolving landscape of combining chemotherapy with immune checkpoint inhibitors in advanced PDAC. We explore how certain chemotherapies can induce immunogenic cell death, release tumor antigens, and modulate immune cell populations, thereby priming the TME for checkpoint blockade. However, despite this mechanistic synergy, clinical trials to date have yielded largely disappointing results. We synthesize the key resistance mechanisms that underlie this failure, including dense stromal barriers, low tumor mutational burden, redundant immune checkpoint expression, and abundant immunosuppressive cellular networks. The review then highlights the most promising emerging strategies to overcome resistance, such as next-generation bispecific antibodies, stromal-modulating agents, personalized neoantigen vaccines, and biomarker-driven patient selection. By integrating recent clinical evidence with mechanistic insights, this review provides a roadmap for developing more effective, personalized chemo-immunotherapy combinations to transform outcomes in this recalcitrant disease.