Multi‐Omics Profiling of High‐Grade Serous Ovarian Cancer Reveals an Inflammation‐Related Lipid Metabolism Subtype Associated With Platinum Resistance

ABSTRACT Ovarian cancer is the deadliest gynecological malignancy. The main obstacle in treating high‐grade serous ovarian cancer (HGSOC) is platinum resistance. The mechanistic interface between tumor metabolic reprogramming and platinum resistance remains undefined. We integrated proteomic and metabolomic profiling of 97 primary HGSOC tumors to map the molecular landscape. Unsupervised clustering identified three subtypes. Subtype 3 exhibited a higher platinum resistance rate (64.5%), as well as worse overall ( p = 0.001) and recurrence‐free ( p = 0.0001) survival. At the molecular level, both Subtypes 2 and 3 tumors displayed phenotypes of activated lipid metabolism. However, Subtype 3 tumors were unique, exhibiting potential divergence between lipid metabolism and bioenergetics. The arachidonic acid metabolism pathway was upregulated ( p = 2.0 × 10 −6 ), and the key enzyme cyclooxygenase‐2 (COX‐2) was overexpressed ( p < 0.001). Subtype 3 tumors exhibited an inflammation‐associated state with the highest infiltration of M2‐like macrophages ( p = 0.007). Single‐cell transcriptomics revealed increased expression of PTGS2 (encoding COX‐2, p = 0.001) and CD163 ( p < 2.2 × 10 −16 ) in macrophages from platinum‐resistant HGSOC. Multiplex immunofluorescence confirmed that platinum‐resistant tumors had a higher proportion of COX‐2 + cells in M2‐like macrophages ( p = 0.010). These findings define a high‐risk HGSOC subtype characterized by inflammation‐related lipid metabolism. This suggests targeting the arachidonic acid metabolism pathway as a way to overcome platinum resistance.