Harnessing the Immunomodulatory Potential of Radiofrequency Ablation to Improve Therapeutic Outcomes in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) continues to rank among the most lethal cancers with poor prognosis. PDAC is characterized by a thick desmoplastic stroma, severe immunological suppression, and resistance tostandard treatments. The need for innovative therapeutic approaches is highlighted by the tumor microenvironment's (TME) critical role in promoting disease development and reducing the effectiveness oftreatment. A promising locoregional treatment that can induce tumor necrosis and modify the TME is endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA). However, there is still minimal understanding around its wider impact on stromal remodeling and immunological activation. This study investigates the immunomodulatory effects of RFA combined with neoadjuvant chemotherapy in clinical samples and in combination with immune checkpoint blockade using a syngeneic pancreatic cancer mouse model. We demonstrate that when RFA is combined with an αPD-L1 (anti-programmed death-ligand 1) treatment, it causes both local and systemicimmune activation, improving Granzyme B+ cell infiltration, boosting collagen deposition, reducing immunosuppressive cytokine signaling, and promoting anabscopal response in distant, untreated tumors. In accordance with these results, RFA may help the immune system to overcome PDAC's innate immunotherapy resistance. To further analyze the clinical significance of these results,we used human PDAC biospecimens to examine the effects of EUS-RFA in conjunction with chemotherapy in theneoadjuvant setting. An increase in apoptotic cell death as measured by cleaved caspase-3 expression, significant increase in collagen deposition, a decrease in the expression of macrophage migration inhibitory factor (MIF) levels, and elevated hypoxia-inducible factor 2-alpha (HIF2α) expression were among the important componentsof the TME that were examined. Our data shows notable tumor-associated changes post-RFA, highlighting how EUS-RFA may enhance chemotherapeutic efficacy in PDAC. This study underscores RFA’s potential to reshape the tumor microenvironment, strengthen anti-tumor immunity, and improve therapeutic outcomes when combined with immunotherapy and chemotherapy. These findings lay the groundwork for developing innovative therapeutic approaches and refining combination treatment strategies for this extremely resistant cancer.