Obesity is associated with increased incidence and mortality of multiple tumor types, and competes with smoking tobacco as the leading preventable risk factor for all cancer-related deaths. In breast cancer, epidemiological studies have shown that obesity is linked to enhanced metastasis to lung and liver. However, it is not known how to improve cancer outcomes in the obese patient population as the mechanistic link between obesity and cancer progression is currently lacking. Using genetic and diet-induced obesity mouse models, it was previously shown that obesity promotes pulmonary metastasis of breast cancer by inducing lung neutrophilia via a IL5–GM-CSF signaling axis. We have now determined that neutrophils are reprogrammed by obesity within the lung to produce elevated levels of reactive oxygen species (ROS) and release neutrophil extracellular traps (NETs). This in turn weakens endothelial barrier integrity, leading to enhanced microvascular permeability and tumor cell extravasation into the lung parenchyma. This effect can be reversed by targeting ROS via pharmacological or genetic approaches, or by preventing NETosis using PAD4 inhibitors. To confirm the translational relevance of our findings, we performed imaging mass cytometry on lung metastasis samples from cancer patients, and observed a significant correlation between body mass index and NETosis, neutrophil oxidative burst, and ROS status. Given the high prevalence of obesity on an international scale, our data provide insight into mechanisms of cancer progression for a significant proportion of the adult population, including (potentially) those who are metabolically obese but normal weight. Citation Format: Sheri A. McDowell, Robin Luo, Jonathan D. Spicer, Andrew J. Dannenberg, Logan A. Walsh, Daniela F. Quail. Linking obesity-associated inflammation with cancer metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA018.