Published online May 14, 2021. doi: 10.3748/wjg.v27.i18.2105
Peer-review started: January 8, 2021
First decision: February 23, 2021
Revised: March 9, 2021
Accepted: April 21, 2021
Article in press: April 21, 2021
Published online: May 14, 2021
Pancreatic ductal adenocarcinoma (PDAC) is projected to emerge as the second leading cause of cancer-related death after 2030. Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC. To date, combination chemotherapy remains the mainstay of treatment for most PDAC patients. Compared to other cancer types, treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorter-lived. Aside from typically harboring genetic alterations that to date remain un-druggable and are drivers of treatment resistance, PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance. However, emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes. These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression. The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells, stromal fibroblasts, and immune cells. This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease. Here, we provide a concise review on lessons learned from past stroma-targeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC.
Core Tip: Stromal desmoplasia is not only a prominent histological hallmark of pancreatic cancer, but also a biological barrier to therapies. Various strategies aimed at targeting the stroma to improve therapeutic outcomes have been largely unsuccessful. Here we comprehensively reviewed the rationales and lessons learned from various stromal-targeting strategies and provide prospects on improving these approaches in future clinical trials.