Figure 1.

Mechanisms of chemoresistance in the ovarian cancer microenvironment, and strategies to overcome resistance. (A) Within ovarian TME, fibroblasts are converted into CAFs by a yet unknown mechanism. CAFs utilize cystine to generate cysteine and glutathione, which are then released into the extracellular milieu. The uptake of glutathione and cysteine by tumor cells leads to elevated intracellular glutathione level. As a consequence, levels of intracellular cisplatin are decreased, resulting in lower levels of DNA damage and cell death, and cisplatin resistance. This chemoresistant stroma comprises a high number of CAFs and a limited number of infiltrated CD8⁺ T lymphocytes. (B) CD8⁺ T cell-derived IFN-γ activates the IFN-γ R1/STAT1 signaling pathway in CAFs, leading to reduction of extracellular cystine consumption, downregulation of cysteine synthesis and degradation of glutathione. Through this mechanism, intracellular cisplatin accumulation is restored in ovarian cancer cells, leading to ovarian cancer cell apoptosis. This chemosensitive stroma comprises high number of CD8+ lymphocytes, which predict responsiveness to cisplatin independently of CAF content.