Local ablation breaks immune tolerance in pancreatic cancer

Pancreatic cancer (PC) is characterised by late diagnosis, neoplastic heterogeneity, and a highly immunosuppressive tumour microenvironment, resulting in poor clinical outcomes. Local ablative techniques have been proposed to treat unresectable PC patients, although their impact on activating the host immune system and overcoming resistance to immunotherapy remains elusive. Here, we showed that local ablation induced a short-term inflammatory process characterized by increased circulating myeloid cells and plasma levels of high mobility group box (HMGB)-1 molecule associated with a longer time to progression in PC patients. Additionally, local ablation synergised with immunotherapy to restrict tumour progression, and improved the survival of PC-bearing mice by evoking a T lymphocyte-dependent anti-tumour immune response. By integrating spatial transcriptomics with histological techniques, we pinpointed how combination therapy could reshape TME towards an anti-tumour milieu characterized by the preferential entrance and colocalization of activated T lymphocytes and myeloid cells endowed with antigen presentation features instead of T regulatory lymphocytes and CD206-expressing tumour-associated macrophages. In addition, treatment-dependent TME repolarization extended to neoplastic cells, promoting a shift from squamous to a more differentiated classical phenotype. Therefore, RFA might circumvent the current limitations of immunotherapy in PC.