Challenges and opportunities in combining radiotherapy and immunotherapy for localized pancreatic cancer

Even when presenting in the clinic with localized disease, patients with pancreatic ductal adenocarcinoma (PDAC) experience extremely poor survival, owing to local recurrence and/or distant progression driven by micrometastatic lesions despite aggressive systemic chemotherapy. Neither radiation therapy nor immunotherapy have yet been successful at extending the survival of patients with localized PDAC, at least in part owing to a series of (immuno)biological mechanisms of innate and acquired resistance. However, an expanding preclinical and clinical literature from PDAC and other oncological indications identifies novel approaches through which radiation therapy-immunotherapy combinations could improve local and systemic disease control in patients with PDAC. Here, we propose to reposition radiation therapy as an immunological platform rather than a purely cytotoxic treatment modality. To this aim, we critically discuss the rationale, challenges and opportunities for combining radiotherapy with immunotherapy to improve the clinical management of localized pancreatic cancer, focusing on the identification of optimal radiation therapy backbones and innovative immunotherapy approaches that might unlock superior therapeutic interactions between these treatment modalities.