SLC46A3 encodes a lysosomal membrane transporter that plays critical roles in cellular drug transport and metabolism. The protein functions as a proton-coupled transporter that facilitates the escape of various substrates from lysosomes to the cytoplasm 1. SLC46A3 is essential for the efficacy of antibody-drug conjugates (ADCs), particularly trastuzumab emtansine (T-DM1), by transporting cytotoxic catabolites from lysosomes to the cytoplasm where they exert their therapeutic effects 23. The transporter recognizes lipophilic steroid conjugates and bile acids as endogenous substrates and demonstrates pH-dependent transport activity 1. Additionally, SLC46A3 modulates hepatic copper homeostasis by sequestering copper ions in lysosomes, which can affect mitochondrial function and lipid metabolism 4. Loss of SLC46A3 function represents a significant resistance mechanism for ADC therapy, as demonstrated in CRISPR screens identifying it as a critical sensitivity factor 2. The transporter can be inhibited by macrolide antibiotics, which accumulate in lysosomes and attenuate T-DM1 cytotoxicity, suggesting potential drug-drug interactions in cancer therapy 3. SLC46A3 expression patterns also show tissue-specific methylation differences that can distinguish gastric from esophageal adenocarcinomas 5.