Our data and the literature suggest that multiple factors may contribute to determine anti-CXCR4 ADC cytotoxicity to normal and cancerous CXCR4+ cells, beyond differences in relative CXCR4 expression levels: mitotic index, rates of CXCR4:ADC complex internalization and processing, CXCL12 levels in tumour microenvironment, expression/activity of multi-drug resistance ABC transporters and presence of genetic alterations impacting lysosome sorting pathway. The gene discussed is CXCL12; the disease is neoplasm.