Abstract

Neoadjuvant chemotherapy (NACT) is a standard treatment for high-grade serous ovarian cancer (HGSOC), yet determinants of therapeutic response remain incompletely defined. Here, multi-omics analysis of 102 tumor samples revealed that NACT reshapes the tumor microenvironment, enhancing B- and NK-cell infiltration and activating antigen presentation and BCR/TCR signaling pathways. Notably, Nab-paclitaxel outperformed paclitaxel in promoting B cell-mediated humoral immunity. Unsupervised clustering identifies two biologically distinct subtypes: an immune-active chemotherapy response score (CRS)-high subtype characterized by CD19 + B-cell enrichment and complement activation, and a metabolically rewired CRS-low subtype exhibiting heightened oxidative phosphorylation (OXPHOS) and mitochondrial remodeling. Platinum-resistant tumors display pronounced OXPHOS dependency, indicating a bioenergetic vulnerability. Pharmacologic inhibition of mitochondrial Complex I with IACS-010759, or genetic silencing of its core subunit NDUFA8, selectively restores carboplatin sensitivity in resistant cells and xenograft models. Complex I disruption suppresses mitochondrial respiration, induces membrane depolarization and oxidative stress, and triggers stress-adaptive mitophagy, thereby lowering the threshold for platinum-induced cytotoxic stress. Clinically, CD19 + B-cell infiltration and NDUFA8 expression are significantly associated with platinum responsiveness and NACT outcome. Together, these findings define immune activation and mitochondrial bioenergetic dependency as dual determinants of chemotherapy response and highlight Complex I–targeted intervention as a rational strategy to overcome platinum resistance in HGSOC.