Breaking the immune desert: Strategies for overcoming the immunological challenges of pancreatic cancer

Abstract

Pancreatic cancer is characterised by its highly aggressive nature and extremely poor prognosis, with a uniquely complex tumour immune microenvironment that manifests as a prototypical “immune desert.” This immune-desert phenotype primarily arises from the inherently low immunogenicity of the tumour, the formation of a dense fibrotic stroma, severe deficiency in immune cell infiltration, and profound immunosuppressive effects of the metabolic landscape. Specifically, dysregulated tryptophan metabolism, such as indoleamine 2,3-dioxygenase (IDO)-mediated catabolism, and excessive lactate accumulation contribute to impaired T-cell functionality. Collectively, these factors severely limit the efficacy of current immunotherapy strategies, particularly those based on immune checkpoint inhibitors, which have demonstrated significantly lower clinical response rates in pancreatic cancer than in other malignancies.

In response to these therapeutic challenges, this review explores integrated treatment strategies that combine metabolic reprogramming, tumour microenvironment remodelling, and next-generation immune checkpoint blockades, such as LAG-3, TIM-3, and VISTA. These emerging approaches hold substantial promise for clinical application. For example, targeting key metabolic pathways, including glycolysis (Warburg effect) and glutamine metabolism, may help restore T-cell activity by alleviating metabolic stress within the tumour milieu. Additionally, localised administration of immune stimulators such as interleukin-12 (IL-12) and CD40 agonists may enhance immune cell infiltration and promote tumour-specific immune activation.

Future research should prioritise large-scale, multicentre clinical trials to validate the therapeutic efficacy of these innovative strategies, aiming to achieve meaningful breakthroughs in pancreatic cancer immunotherapy and significantly improve long-term survival and clinical outcomes in affected patients.