Herein, using in vitro TNBC models including cell lines with GPX4 or PC suppressed, together with murine models of obesity and TNBC growth and metastasis, we aimed to characterize (i) interactions between GPX4, PC, and lipid oxidative stress in TNBC cells, and (ii) the effect of GPX4 suppression, alone or in combination with chemotherapy or immunotherapy, on TNBC progression. Here, GPX4 is linked to obesity due to melanocortin 4 receptor deficiency.