Radiotherapy may be able to do far more than simply destroy tumor cells. A review published in Nature Reviews Gastroenterology & Hepatology explores how combining radiotherapy with immunotherapy could improve outcomes for patients with pancreatic cancer
Pancreatic cancer remains one of the most aggressive malignancies, with a particularly poor prognosis, even when diagnosed at a localized stage. In a landmark review published in Nature Reviews Gastroenterology & Hepatology, researchers from GIGA and Liège University Hospital, together with colleagues from Gustave Roussy (Paris, France) and Fox Chase Cancer Center (Philadelphia, USA), propose a new therapeutic perspective: viewing radiotherapy not merely as a treatment that destroys cancer cells, but as a tool capable of stimulating the immune system and enhancing the efficacy of immunotherapy.
Coordinated by Dr. Gilles Colin and Dr. Pierre Foidart, the review examines the latest advances from both basic and clinical research. Its objective is to better understand how radiotherapy can modulate antitumor immune responses in order to identify strategies for effectively combining it with immunotherapy in localized pancreatic cancer and, ultimately, reducing the risk of metastatic relapse.
A Particularly Challenging Cancer to Treat
Pancreatic cancer is resistant to many therapeutic approaches. Even when the tumor is localized and amenable to surgery, the risk of recurrence remains high. One reason lies in its highly complex tumor microenvironment, characterized by a dense stromal compartment and biological mechanisms that naturally suppress immune cell activity.
In this context, immunotherapies that have transformed the treatment landscape of several cancers have so far shown limited efficacy in pancreatic cancer. Likewise, the benefits of radiotherapy remain modest when delivered according to conventional treatment schedules.
The authors emphasize, however, that radiotherapy exerts biological effects that remain underexploited. When delivered under specific conditions, it can increase the visibility of cancer cells to the immune system, promote the activation of immune effector cells, and reshape the tumor microenvironment in ways that support antitumor immunity.
The challenge is therefore no longer simply to combine two treatments, but to design radiotherapy in a way that maximizes its immunological potential. Radiation dose, fractionation, treatment sequencing, irradiation precision, and target volume selection may all play critical roles in determining the success of future therapeutic strategies.
“It is not enough to simply combine radiotherapy and immunotherapy. It is equally important to better understand how radiotherapy delivery parameters influence the immune response in order to optimize the interaction between these two treatment modalities,” explains Dr. Pierre Foidart.
Innovative Strategies Already Under Investigation
The review highlights several promising approaches currently being evaluated in preclinical and clinical studies. Some seek to employ more targeted and better tolerated forms of radiotherapy, while others combine radiotherapy with next-generation immunotherapies, therapeutic vaccines, or treatments designed to reprogram the tumor microenvironment.
Other strategies are exploring inhibitors targeting key biological pathways involved in pancreatic cancer, particularly those linked to KRAS, a protein that is frequently altered in this disease.
According to the authors, future progress will also depend on the ability to better identify patients who are most likely to benefit from these approaches. The development of predictive biomarkers, the analysis of circulating tumor DNA, and the implementation of adaptive clinical trial designs could help further personalize treatment and optimize therapeutic combinations.
“Pancreatic cancer remains a major challenge in oncology. However, recent advances now allow us to view radiotherapy from an entirely new perspective. By considering it as a platform capable of modulating both the tumor microenvironment and responsiveness to immunotherapy, we are opening new avenues to improve disease control,” says Dr. Gilles Colin.
A Roadmap for Future Research
More than a simple review of the current state of knowledge, this publication provides a genuine roadmap for future research. The investigators advocate an integrated approach in which radiotherapy, immunotherapy, precision medicine, and technological innovation are developed together to overcome the resistance mechanisms that characterize pancreatic cancer.
In the long term, such strategies could help improve local disease control, limit the emergence of clinically undetectable metastatic lesions present at diagnosis, and ultimately extend survival for patients facing one of the most difficult cancers to treat.
Nature Reviews Gastroenterology & Hepatology
Challenges and opportunities in combining radiotherapy and immunotherapy for localized pancreatic cancer
2-Sep-2026