Remodeling the pancreatic tumor microenvironment by chemotherapy: New opportunities for combination therapy.

The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) have risen steadily, yet the five-year survival rate remains a dismal 9%, underscoring the urgent need for novel therapeutic strategies. While immunotherapy has shown remarkable efficacy across multiple cancer types, it has largely failed to demonstrate meaningful clinical benefit as a monotherapy in PDAC. Emerging evidence indicates that combining chemotherapy with immunotherapy improves overall survival, suggesting that chemotherapy exerts meaningful modulatory effects on the PDAC tumor microenvironment (TME) that may enhance immunotherapy responsiveness. This review systematically characterizes the immunosuppressive and stromal features of the PDAC TME, delineates the multifaceted effects of chemotherapy on TME remodeling, and identifies potential combinatorial targets that may synergize with chemotherapy to improve therapeutic outcomes.