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Ascites represents an important mediator and a unique tumor microenvironment (TME) for invasion and metastasis. This study performed high\u2010resolution mass spectrometry (MS) on pre\u2010chemotherapy ascites cells from ovarian cancer patients. Integrating proteomic profiling, clinical data, and single\u2010cell analysis revealed that platinum\u2010resistant ascites displayed a distinct microenvironmental: the macropinocytosis\u2010related protein Src homology 3 domain\u2010containing YSC84\u2010like 1 (SH3YL1) was upregulated, whereas the immune\u2010activation marker CD44 was downregulated in resistant cases. Single\u2010cell 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\u2010rich, with immunofluorescence plus flow cytometry confirming its association with immune exhaustion. Cellular experiments confirmed that SH3YL1\u2010mediated macropinocytosis promoted lipid uptake, and its inhibition partially restored cisplatin sensitivity. A combined model of immune exhaustion, macropinocytosis, and lipid catabolism suggests these ascites\u2010associated features could somewhat predict the platinum sensitivity in ovarian cancer tissues. We therefore propose the hypothesis that, in a lipid\u2010rich ascites microenvironment, immune exhaustion occurs while tumor cells activate macropinocytosis and lipid catabolism\u2014forming a network of resistance mechanisms that may serve as potential predictive markers or intervention targets for platinum resistance.<\/jats:p>","DOI":"10.1002\/mco2.70657","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T09:56:31Z","timestamp":1772963791000},"source":"Crossref","is-referenced-by-count":2,"title":["Active Macropinocytosis, Lipid Catabolism, and Exhausting Immune Microenvironment of Ascites Tumor Cells Are Involved in Resistance to Platinum\u2010Based Therapy in Patients With High\u2010Grade Serous Ovarian Cancer"],"prefix":"10.1002","volume":"7","author":[{"given":"Ruiqi","family":"Zheng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Molecular Oncology Department of Etiology and Carcinogenesis National Cancer Center\/National 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