Abstract 6786: Neutrophil extracellular trap inhibition mitigates tumor necrosis and metastasis in colorectal cancer

Abstract Neutrophils (polymorphonuclear cells, PMNs) have been shown to directly induce necrosis through the formation of neutrophil extracellular traps (NETs) in murine models of breast and lung cancer. Although necrosis is a well-recognized predictor of poor outcomes in cancer, it is typically regarded as a passive and non-targetable process. To determine whether NETs actively drive necrosis in colorectal cancer (CRC), we evaluated the pathogenic impact of NET formation in human CRC specimens and complementary preclinical models.In blood samples from patients with CRC, we identified elevated populations of neutrophils primed for NET formation, including an expanded CD177Low subset that retained strong NET-forming capacity with reduced extravasation ability. Histologic and immunofluorescent analyses of human CRC and colorectal liver metastases demonstrated abundant NET accumulation within necrotic regions, forming intravascular deposits. The extent of necrosis correlated with metastatic disease, independent of tumor size. Single-cell RNA sequencing and spatial transcriptomic profiling of human primary CRC and liver metastases showed that NET-rich necrotic tumors activate transcriptional programs associated with myelopoiesis (CSF1, CXCL2, CXCL12), hypoxia signaling, migration, and epithelial-to-mesenchymal transition—features linked to increased metastatic potential. In a mismatch-repair-proficient orthotopic CRC model using AKPS (APCKO KRASG12D P53KO SMAD4KO) organoids implanted via colonoscopic injection, tumor progression was marked by rising circulating PMNs, bone marrow skewing toward myelopoiesis, and increasing NET deposition within necrotic tumor regions. Genetic and pharmacologic inhibition of NET formation reduced intratumoral necrosis and significantly decreased metastatic burden. Collectively, these findings demonstrate that NETs are active drivers of necrosis and metastatic evolution in CRC, reframing necrosis as an immunopathologic process rather than an unavoidable consequence of tumor growth. Targeting NET formation represents a promising translational strategy to improve disease control and oncologic outcomes for patients with CRC. Citation Format: Emma Gazzara, Adrover Jose, Sebastian Dziadowicz, Song Han, Alex Liu, Zakeria Aminzada, Nischal Bhandari, Venktesh Shirue, Bhupinder Shergill, Matthew Curtis, Steven C. George, Alexander Cicala, Arvind Rishi, Craig Devoe, Hai Huang, Matthew Weiss, Emil Lou, David A. Tuveson, Semir Beyaz, Peter Maxwell Kienitz Westcott, Mikala Egeblad, Sepideh Gholami. Neutrophil extracellular trap inhibition mitigates tumor necrosis and metastasis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6786.