cGAS/STING-activated macrophages form lipophagosomes to regulate TME and promote progression in obesity-associated pancreatic cancer

Background: Obesity significantly accelerates pancreatic cancer progression and worsens patient prognosis. However, the specific mechanisms by which macrophages regulate the tumor microenvironment (TME) in obese pancreatic cancer patients remain unclear. Understanding how macrophage-mediated TME remodeling contributes to accelerated disease progression in obesity-associated pancreatic cancer is crucial for developing targeted therapeutic strategies. Methods: We investigated macrophage phenotypic changes and TME regulation in obesity-associated pancreatic cancer progression. We analyzed cGAS/STING pathway activation in tumor-associated macrophages, characterized mediating lipophagosome formation through lipid engulfment, and examined the resulting immunosuppressive TME. The study evaluated T cell dysfunction, regulatory T cell expansion, and the mechanistic role of tumor-derived mitochondrial DNA in macrophage activation. Results: We identified a comprehensive mechanism whereby macrophages promote obese pancreatic cancer patient progression through cGAS/STING-mediated lipophagosome formation and TME regulation. Obesity-associated pancreatic cancer develops within a characteristic immunosuppressive environment where macrophages undergo cGAS/STING pathway activation, leading to their differentiation into foam macrophages. These STING-activated macrophages simultaneously cause CD8+ T cell exhaustion and promote regulatory T cell proliferation while competitively uptaking lipids, thereby depleting metabolic resources essential for CD8+ T cell function. Through this lipid engulfment process, STING-activated macrophages form specialized organelles called lipophagosomes, which further enhance Treg proliferation and amplify immunosuppression within the TME. Mechanistically, tumor cells in the obesity environment release mitochondrial DNA that serves as the primary trigger for macrophage cGAS/STING activation, establishing a feed-forward loop that maintains and intensifies the obesity-induced immunosuppressive environment, ultimately driving accelerated tumor progression. Conclusions: Our findings demonstrate that macrophages promote obese pancreatic cancer patient progression through cGAS/STING-activated lipophagosome formation, which remodels the TME into an immunosuppressive state. This macrophage-centric mechanism provides novel therapeutic targets for treating obesity-associated pancreatic cancer progression.