Serial Thermal Ablation Induces Abscopal Antitumor Immunity and Reveals Targetable CSF1R-Dependent Resistance in Pancreatic Cancer

  • bioRxiv. 2026 Apr 8:2026.04.05.713683. doi: 10.64898/2026.04.05.713683.
Lincoln N Strickland  1  2  3 ,  Wendao Liu  4  5 ,  MacKenzie V Demmel  1  2 ,  Alyssa M Waller  1  2 ,  Shwetapadma Dash  1  6 ,  Khadija Turabi  1  2  3 ,  Nicolette R Mardik  7 ,  Casey J Van Kirk  1 ,  Baylee O'Brien  7 ,  Julie Rowe  7 ,  Putao Cen  7 ,  Kelsey A Klute  2  8 ,  Jesse L Cox  1 ,  Zhongming Zhao  5 ,  Sunil R Hingorani  2  9 ,  Curtis J Wray  10 ,  Nirav C Thosani  7  11 ,  Jennifer M Bailey-Lundberg  1  2
Affiliations
  • 1. Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE.
  • 2. Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE.
  • 3. Cancer Research Graduate Program, The Eppley Institute, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE.
  • 4. The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas.
  • 5. Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX.
  • 6. Biochemistry and Molecular Biology Graduate Program, University of Nebraska Medical Center, Omaha, NE.
  • 7. Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX.
  • 8. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.
  • 9. Pancreatic Cancer Center of Excellence, University of Nebraska Medical Center, Omaha, NE.
  • 10. Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX.
  • 11. Center for Interventional Gastroenterology, The University of Texas Health Science Center, Houston, TX.
PMID: 41993287 DOI: 10.64898/2026.04.05.713683
Abstract

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-Kras G12D/+ ; LSL-Trp53 R172H/+ ; 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.

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