The endosomal-lysosomal system in ADC design and cancer therapy

INTRODUCTION: This discourse delves into the intricate connections between the endosomal-lysosomal system and antibody-drug conjugates (ADCs), shedding light on an essential yet less understood dimension of targeted therapy. While ADCs have revolutionized cancer treatment, resistance remains a formidable challenge, often involving diverse and overlapping mechanisms. AREAS COVERED: This discourse highlights the roles of various components within the endosomal machinery, including Rab proteins, in ADC resistance development. It also explores how the transferrin-transferrin receptor and epidermal growth factor-epidermal growth factor receptor complexes, known for their roles in recycling and degradation process, respectively, can offer valuable insights for ADC design. Selected strategies to enhance lysosomal targeting are discussed, and potentially offer solutions to improve ADC efficacy. EXPERT OPINION: By harnessing these different insights that connect ADCs with the endosomal-lysosomal system, the field may benefit to shape the next-generation of ADC design for increased efficacy and improved patient outcomes.