Abstract Using tumor cell-restricted overexpression of glutathione peroxidase 4 (GPx4), we investigated the contribution of tumor cell eicosanoids to solid tumor growth and malignant progression in two tumor models differing in tumorigenic potential. By lowering cellular lipid hydroperoxide levels, GPx4 inhibits cyclooxygenase (COX) and lipoxygenase (LOX) activities. GPx4 overexpression drastically impeded solid tumor growth of weakly tumorigenic L929 fibrosarcoma cells, whereas B16BL6 melanoma solid tumor growth was unaffected. Yet, GPx4 overexpression did markedly increase the sensitivity of B16BL6 tumors to angio-destructive TNF-α therapy and abolished the metastatic lung colonizing capacity of B16BL6 cells. Furthermore, the GPx4-mediated suppression of tumor cell prostaglandin E 2 (PGE 2) production impeded the induction of COX-2 expression by the tumor stress conditions hypoxia and inflammation. Thus, our results reflect a PGE 2-driven positive feedback loop for COX-2 expression in tumor cells. This was further supported by the restoration of COX-2 induction capacity of GPx4-overexpressing L929 tumor cells when cultured in the presence of exogenous PGE 2. Thus, although COX-2 expression and eicosanoid production may be enabled by PGE 2 from the tumor microenvironment, our results demonstrate the predominant tumor cell origin of protumoral eicosanoids, promoting solid tumor growth of weakly tumorigenic tumors and malignant progression of strongly tumorigenic tumors.