MSMO1 promotes chemotherapy resistance through modulation of T-MAS metabolism via PERK/elF2α/ATF4/CHOP pathway.

Tumor metabolism is characterized by dynamic plasticity, but there is a lack of appropriate tools to detect metabolic changes across different tumor stages, limiting the application of metabolism-targeted therapies. Our study introduces a noninvasive liquid biopsy approach, utilizing exosomes to reflect the metabolic profile of primary tumors at the transcriptome level. We observed a significant correlation between cholesterol synthesis and the response to neoadjuvant chemotherapy in breast cancer, particularly with non-pathologic complete response (non-pCR). Methylsterol monooxygenase 1 (MSMO1) was identified as a key factor influencing breast cancer chemosensitivity. MSMO1 regulates the metabolism of 14-demethyllanosterol (T-MAS), contributing to chemotherapy resistance via the PERK/eIF2α/ATF4/CHOP signaling pathway. Notably, plasma exosomal levels of MSMO1 may serve as a predictive biomarker for identifying patients who may benefit from T-MAS-mediated chemosensitization strategies, offering a promising approach for personalized breast cancer treatment.