Active Macropinocytosis, Lipid Catabolism, and Exhausting Immune Microenvironment of Ascites Tumor Cells Are Involved in Resistance to Platinum‐Based Therapy in Patients With High‐Grade Serous Ovarian Cancer

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.