Strickland, L. N.; Liu, W.; Demmel, M. V.; Waller, A. M.; Dash, S.; Turabi, K.; Mardik, N. R.; Van Kirk, C. J.; O'Brien, B.; Rowe, J.; Cen, P.; Klute, K. A.; Cox, J. L.; Zhao, Z.; Hingorani, S. R.; Wray, C. J.; Thosani, N. C.; Bailey-Lundberg, J. M.

Thermal ablation is increasingly used for local control of pancreatic ductal adenocarcinoma (PDAC), but its capacity to induce systemic antitumor immunity and the mechanisms limiting this response remain incompletely defined. Using a bilateral LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) flank tumor model, we show that serial radiofrequency ablation (RFA) enhances local tumor control and induces a robust abscopal response. This effect was associated with increased activation of CD8 T cells and natural killer cells, and was abrogated by CD8 T cell depletion. Single-cell RNA sequencing revealed expansion of cytotoxic immune programs alongside induction of a CSF1-driven myeloid response consistent with adaptive immune resistance. Although CSF1R inhibition alone was insufficient to improve tumor control, combinatorial blockade of PD-L1 and CD73 augmented systemic antitumor responses, and the addition of CSF1R inhibition in this context further enhanced both local and distant tumor control. These findings identify a CSF1-dependent myeloid resistance program that constrains ablation-induced systemic immunity and demonstrate that rational combination immunotherapy can potentiate the systemic efficacy of tumor ablation in PDAC.