Breaking the stromal barrier in pancreatic cancer: Advances and challenges

Pancreatic cancer (PC) remains a leading cause of mortality worldwide due to the absence of early detection methods and the low success rates of traditional therapeutic strategies. Drug resistance in PC is driven by its desmoplastic stroma, which creates a barrier that shields cancer niches and prevents the penetration of drugs. The PC stroma comprises heterogeneous cellular populations and non-cellular components involved in aberrant ECM deposition, immunosuppression, and drug resistance. These components can influence PC development through intricate and complex crosstalk with the PC cells. Understanding how stromal components and cells interact with and influence the invasiveness and refractoriness of PC cells is thus a prerequisite for developing successful stroma-modulating strategies capable of remodeling the PC stroma to alleviate drug resistance and enhance therapeutic outcomes. In this review, we explore how non-cellular and cellular stromal components, including cancer-associated fibroblasts and tumor-associated macrophages, contribute to the immunosuppressive and tumor-promoting effects of the stroma. We also examine the signaling pathways underlying their activation, tumorigenic effects, and interactions with PC cells. Finally, we discuss recent pre-clinical and clinical work aimed at developing and testing novel stroma-modulating agents to alleviate drug resistance and improve therapeutic outcomes in PC.