Single-Nuclei RNA Sequencing Reveals Obesity-Driven Reprogramming of Estrogen Signaling in Endometrioid Adenocarcinoma

Obesity is a major risk factor for endometrioid adenocarcinoma, but how it alters estrogen-driven signaling and tumor–immune dynamics remains unclear. To address this, we performed single-nuclei RNA sequencing on thirteen primary tumors from postmenopausal patients with normal and obese body mass indices. Tumors from obese patients exhibited widespread transcriptional remodeling across tumor and immune compartments. Notably, weighted gene correlation network analysis revealed that estrogen receptor–associated gene modules in tumors from obese patients were compositionally distinct from those in normal-weight patients, suggesting that estrogen may signal through alternative regulatory networks in the obese tumor microenvironment. Additional obesity-associated features included epithelial-to-mesenchymal transition, metabolic stress, immune suppression, and altered cell–cell communication. These findings demonstrate that obesity not only amplifies estrogenic signaling but may rewire its molecular context in tumor epithelial cells. Our work identifies mechanistic differences in hormone signaling linked to obesity and highlights pathways that may inform future strategies for therapeutic targeting in obesity-associated endometrial cancer.