Abstract LB467: Multi-omics analysis of brain metastasis elucidates obesity induced linoleic acid and arachidonic acid metabolism crosstalk in tumor microenvironent restrains CD8T cell expansion

Abstract Background: Brain metastasis (BrM) is one of the most crucial complications of tumor patient, necessitating innovative pharmacological interventions. Recent evidence suggests that obesity significantly modifies the tumor microenvironment (TME) and modulates inflammatory responses and anti-tumor immunity through fatty acid-mediated mechanisms. Understanding the complex metabolic interactions within the BrM tumor microenvironment could potentially lead to the development of novel therapeutic strategies. Methods: We conducted a retrospective analysis of 67 brain metastases patients at Peking Union Medical College Hospital, examining body mass index (BMI) and clinical parameters' impact on survival outcomes. Multi-omics data, including transcriptomic, proteomic, and metabolomic profiles, were collected from partially paired tumor and peri-tumor samples from 127 participants. Comparative analyses were performed between tumor and peritumor regions and between obese and normal-weight groups. Additionally, single-cell transcriptomic profiling of nine BrM samples was undertaken to elucidate protein-mediated and metabolic intercellular communication within the tumor microenvironment. Results: Survival analyses revealed that BMI serves as a significant predictor of poor prognosis in BrM patients. Clustering analysis of patient transcriptomic profiles identified upregulation of linoleic acid and arachidonic acid metabolism pathways in obese patients. Enrichment analysis demonstrated elevated oxidative stress in the obesity-associated microenvironment. Further survival analyses indicated that PTGES2 and PTGES3, key enzymes in arachidonic acid metabolism, significantly correlates with poor clinical outcomes. Proteomic analysis revealed increased expression of fatty acid binding protein 4 (FABP4), which facilitates linoleic acid transport. Metabolomic profiling validated the enrichment of linoleic acid and arachidonic acid metabolism in obese tumor samples, with linoleic acid emerging as a predictor of poor prognosis. Additionally, elevated levels of glutamine and its downstream glutathione metabolism were observed in obese tumor samples, suggesting an adaptive response to oxidative stress. Single-cell RNA sequencing analysis revealed that tumor cells function as primary sensors and consumers of linoleic acid, potentially enhancing tumor invasiveness as recently reported. Furthermore, CD8+ T cells and NK cells were found to be recipients of Prostaglandin E2/E3, which, consistent with previous reports, suppresses their proliferation and function. Conclusion: Our data provides highlighted the importance of linoleic acid an arachidonic acid metabolism modulation in brain metastasis and decipher potential metabolic crosstalk between different type of cells in the tumor microenvironment. These insights suggest that therapeutic strategies targeting these metabolic communication pathways may offer promising interventional opportunities for brain metastasis patients. Citation Format: Zhanao Xu, Yuekun Wang, Zihao Wang, Peng Liu, Wenbin Ma, Yidong Zhou, Yu Wang. Multi-omics analysis of brain metastasis elucidates obesity induced linoleic acid and arachidonic acid metabolism crosstalk in tumor microenvironent restrains CD8T cell expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB467.