ABSTRACT Platinum resistance remains a clinical challenge in ovarian cancer. Ascites represents an important mediator and a unique tumor microenvironment (TME) for invasion and metastasis. This study performed high‐resolution mass spectrometry (MS) on pre‐chemotherapy ascites cells from ovarian cancer patients. Integrating proteomic profiling, clinical data, and single‐cell analysis revealed that platinum‐resistant ascites displayed a distinct microenvironmental: the macropinocytosis‐related protein Src homology 3 domain‐containing YSC84‐like 1 (SH3YL1) was upregulated, whereas the immune‐activation marker CD44 was downregulated in resistant cases. Single‐cell analyses and pathway enrichment indicated immune exhaustion in resistant ascites, alongside enhanced macropinocytosis and lipid catabolism in tumor cells. Clinical data also showed that resistant ascites are lipid‐rich, with immunofluorescence plus flow cytometry confirming its association with immune exhaustion. Cellular experiments confirmed that SH3YL1‐mediated macropinocytosis promoted lipid uptake, and its inhibition partially restored cisplatin sensitivity. A combined model of immune exhaustion, macropinocytosis, and lipid catabolism suggests these ascites‐associated features could somewhat predict the platinum sensitivity in ovarian cancer tissues. We therefore propose the hypothesis that, in a lipid‐rich ascites microenvironment, immune exhaustion occurs while tumor cells activate macropinocytosis and lipid catabolism—forming a network of resistance mechanisms that may serve as potential predictive markers or intervention targets for platinum resistance.
Zheng et al. (2026) studied this question.