Targeting the Heme biosynthesis pathway: strategies to enhance 5-ALA-mediated photodynamic therapy

Photodynamic therapy (PDT) is an efficient clinical treatment option for cancerous tumors. At present, 5-aminolevulinic acid (5-ALA) is the drug most frequently utilized in PDT. 5-ALA serves as a precursor for porphyrin, heme, and bile pigments, and is converted into protoporphyrin IX (PpIX) for the synthesis of heme. PpIX is a valuable diagnostic tool for intraoperative tumor visualization and photodynamic therapy because of its strong fluorescence and photosensitivity. A highly promising and actively investigated preclinical strategy is to modulate the heme biosynthesis pathway to promote 5-ALA-mediated PpIX accumulation. In this review, we aim to summarize previous studies and elucidate the mechanisms underlying these processes. We highlight the key synthases within the heme biosynthesis pathway and provide a comprehensive overview of strategies designed to improve 5-ALA-mediated PpIX fluorescence imaging and photodynamic treatment through the targeted regulation of these metabolic processes.