Cholesteryl ester accumulation as a biomarker for personalized selection of fertility-preserving therapies in endometrioid endometrial carcinoma.

Fertility-preserving treatments for young women with endometrioid endometrial carcinoma (EEC) have limited effectiveness, with only ∼50% of patients responding to first-line progesterone therapy. The absence of reliable methods to predict clinical response during the six-month treatment window creates substantial clinical uncertainty. Here, we developed EEC patient-derived tumor-like cell clusters (PTCs). Utilizing label-free hyperspectral stimulated Raman scattering microscopy in PTCs, we identified cholesteryl ester as an independent biomarker for progesterone response, achieving 86.2% predictive accuracy in a retrospective clinical cohort. Strikingly, progesterone-insensitive patients receiving progesterone-statin combination therapy exhibited a significantly higher 6-month complete response rate compared to those treated with progesterone alone (66.67% vs. 7.69%; HR = 13.00, 95% confidence interval (CI): 2.80-60.28, P < 0.001), including one documented case of post-treatment conception culminating in live birth. Mechanistically, fibroblast-specific cholesteryl ester accumulation was strongly associated with progesterone insensitivity. These results present a biomarker-guided strategy to optimize personalized fertility-preserving therapies in EEC.