Despite the promise of ferroptosis in cancer therapy, selectively inducing robust ferroptosis in cancer cells remains a significant challenge. In this study, manipulation of fatty acids β-oxidation (FAO) by combination of mild photodynamic therapy (PDT) and inhibition of triglycerides (TGs) synthesis was found to induce robust and iron-independent ferroptosis in cancer cells with dysregulated lipid metabolism for the first time. To achieve that, TGs synthesis inhibitor of xanthohumol (Xan) and FAO initiator of tetrakis (4-carboxyphenyl) porphyrin (TCPP) were co-delivered by a nanoplexes composed of pH-responsive amphiphilic lipopeptide C