Mild microwave hyperthermia promotes mitotic catastrophe, induces time-delayed cGAS-STING activation and restores sensitivity to anti-PDL1 therapy in Pan02 pancreatic cancer model.

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune checkpoint inhibitors (ICIs), representingindicating an unmet clinical need. Hyperthermia therapy, an approved anti-cancer approach with limited adverse effects, has been suggested to be capable of modulating the tumor microenvironment (TiME). This study examined the potential of microwave hyperthermia (Ht) to restructure the TiME of Pan02 PDAC model and restore Pan02 tumor's sensitivity to ICIs, followed by mechanistic investigation. In vitro experiments were performed using a 41 °C water bath, and in vivo studies established the Pan02 murine model treated with 41 °C microwave hyperthermia + /- αPD-L1 therapy. In Ht-treated cells, increased percentages of nucleus envelope blebbing, micronucleation, and multi-/macro-nucleation were observed, and live imaging studies suggested mitotic catastrophe. Ht induced cGAS-STING activation, γH2AX formation, dsDNA release, and genomic damage (comet assay) in a time-delayed fashion 24-48 h after Ht. In the Pan02 model, the Ht and αPD-L1 combination significantly repressed the growth of Ht-treated and abscopal tumors and prolonged mouse survival. The TiME was significantly altered after Ht, featuring upregulated infiltration and maturation of DCs, CD8 + T cells, M1 macrophages, and activated cGAS-STING-IFN signaling. The addition of a STING antagonist abolished this tumor-suppressive effect. SUMO1 expression was significantly repressed after Ht, whereas SUMO1 overexpression attenuated Ht-induced cGAS-STING activation. The effect of Ht has also been validated in certain human PDAC cell lines. Taken together, our study suggests that microwave hyperthermia could be an excellent therapeutic companion of ICIs for PDAC management, associated with a novel mechanism of Ht-induced time-delayed DNA damage and STING activation.