Liposomes containing histidine overcome poly ADP-ribose polymerase inhibitor resistance.

Poly ADP-ribose polymerase inhibitor (PARPi) has shown promising clinical efficacy in patients with BRCA-deficient breast cancer. However, the role of metabolic reprogramming in PARPi resistance remains poorly understood. In this study, we analyzed the amino acid metabolome in samples with varying sensitivity to PARPi, revealing histidine as the most prominently dysregulated amino acid. Disruption of histidine metabolism reprogramming using liposomes containing histidine (Liposome His) effectively resensitized PARPi-resistant cells to olaparib. Mechanistically, Liposome His treatment depleted the tetrahydrofolate (THF) pool, thereby impairing nucleotide synthesis, which was particularly cytotoxic in cells with limited THF availability. Methotrexate and folate depletion further enhanced the in vitro efficacy of Liposome His. In contrast, the folate receptor antagonist mirvetuximab soravtansine exhibited potent anti-proliferative effects against PARPi-resistant cells in vivo, albeit with notable adverse effects. Combination therapy involving Liposome His and mirvetuximab soravtansine demonstrated promising inhibitory effects with manageable tolerability profiles. In addition, we preliminarily demonstrated that Liposome His regulates macrophage polarization by activating the mTOR signaling pathway, and when combined with anti-PD-L1 therapy, it jointly inhibits the pro-tumor phenotype of macrophages.