Combining PI3Kγ Inhibition with Radiotherapy Enhances Tumor Control in Pancreatic Cancer

Immunotherapies have shown significant survival benefits across various tumor types, yet pancreatic cancer remains resistant to immune intervention. Macrophages play a dual role in tumor control and resistance, making the modulation of their activity a strategic focus. The inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) has emerged as a promising approach to repolarize tumor-associated macrophages (TAMs) towards an antitumor phenotype, especially when combined with radiotherapy.

PI3Kγ inhibition alone has limited effectiveness in controlling tumor growth, but its combination with radiotherapy significantly enhances tumor control and extends survival in pancreatic cancer models. This combination therapy promotes the clearance of apoptotic tumor cells by macrophages through efferocytosis, a process that is typically immunologically silent but, in this context, leads to an inflammatory phenotype and improved tumor antigen presentation.

Radiotherapy increases the availability of tumor antigens and stimulates innate immunity, while PI3Kγ inhibition prevents the polarisation of macrophages towards an immunosuppressive phenotype. Together, these treatments enhance the inflammatory capacity of macrophages and their ability to prime CD8+ T cells, leading to improved tumor control.

In preclinical models, the combined treatment of PI3Kγ inhibition and radiotherapy has shown to constrain primary tumor progression and extend survival in a CD8+ T cell-dependent manner. This approach leverages the endogenous cell-clearance mechanism of efferocytosis to promote beneficial tumor control, offering a novel therapeutic strategy for pancreatic cancer.

The findings suggest that the unique combination of radiotherapy and PI3Kγ inhibition could be particularly beneficial for patients with localized pancreatic cancer, potentially overcoming the current limitations of immune intervention in this challenging disease.