Immune Stromal Components Impede Biological Effectiveness of Carbon Ion Therapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma

作者：Katy L. Swancutt, Eslam A. Elghonaimy, James H. Nicholson, Laurentiu M. Pop, Brock J. Sishc, Elizabeth M. Alves, Cassandra Hamilton, A. Rusek, Anthony J. Davis, Raquibul Hannan, Michael D. Story, Todd A. Aguilera · 发表于：Molecular Cancer Therapeutics · 年份：2025 · DOI：10.1158/1535-7163.mct-25-0501 · 被引用次数：3 · 研究领域：Nanoplatforms for cancer theranostics、Radiation Therapy and Dosimetry、Cancer, Hypoxia, and Metabolism

The tumor landscape of pancreatic ductal adenocarcinoma (PDAC) is refractory to conventional photon radiotherapy (RT) because of a fibrotic tumor microenvironment (TME) that promotes chronic hypoxia and reduced immune surveillance. The radiobiological factors unique to carbon ion RT (CIRT), such as high linear energy transfer and less dependence on oxygen, make it well-suited to overcome the PDAC TME. In this study, we utilized clonal syngeneic KPC pancreatic tumor cell lines and tumors to examine this postulate and to identify underlying factors that affect the response of PDAC to CIRT. Although KPC cell lines exhibited radiobiological effectiveness greater than 3, subcutaneous tumors in the mouse hind leg showed lower radiobiological effectiveness-1.3 based on quintupling time-at a linear energy transfer between 70 and 80 keV/μm. Four days after CIRT, we observed widespread transcriptomic changes in the tumor immune microenvironment, suggesting increased infiltration of antitumor immune cells and elevated expression of antitumor T-cell cytokines, MHC class I molecules, and co-stimulatory signals. Fewer immunologic changes were observed following photon irradiation. By 7 days after CIRT, tumor-supportive transcriptomic programs characterized by protumor cytokines, M2 macrophages, and cancer-associated fibroblasts emerged, promoting resistance and limiting the durability of tumor growth delay. These findings suggest that CIRT may offer a favorable platform compared with conve...