Advancing human epidermal growth factor receptor 2-positive gastric cancer therapy: Toward targeted immunotherapy and antibody-drug conjugates

Table 5 Resistance mechanisms to anti-human epidermal growth factor receptor 2 antibody-drug conjugates and emerging counterstrategies

Resistance mechanism	Key molecular/cellular processes	Consequences	Potential overcoming strategies	Ref.
Alterations in target antigen expression	HER2 protein expression levels. Spatial and temporal tumor heterogeneity	Subpopulations with low/no HER2 evade ADC binding, leading to therapeutic escape. Dynamic downregulation under therapeutic pressure drives acquired resistance	Implement dynamic HER2 status monitoring (e.g., via liquid biopsy). Develop ADCs effective against HER2-low tumors. Explore bispecific antibodies or therapies targeting alternative antigens	Ocaña et al[129]
Impaired drug transport	Receptor-mediated endocytosis. ADC intracellular trafficking. Drug efflux pumps (e.g., P-glycoprotein)	Impaired ADC internalization prevents payload delivery. Efflux pumps reduce intracellular payload concentration, diminishing cytotoxicity	Engineer ADCs with improved internalization efficiency. Develop payloads resistant to common efflux pumps. Investigate combination therapies with efflux pump inhibitors	Alrhmoun and Sennikov[32]; Mahalingaiah et al[130]; Chen et al[131]
Lysosomal dysfunction	Lysosomal protease activity. Intralysosomal pH. Lysosomal membrane permeability	Inefficient linker cleavage and payload release, even after successful internalization. Altered pH environment inactivates the payload	Design linkers optimized for specific lysosomal proteases. Utilize pH-sensitive linkers that release payload in early endosomes, bypassing lysosomal dependency	Chen et al[131]; Liu-Kreyche et al[132]
Payload-specific resistance	DDR pathways. Expression of the payload’s molecular target. Activity of drug-metabolizing enzymes	Enhanced DDR capacity repairs payload-induced DNA damage (e.g., from topoisomerase I inhibitors). Target mutation/downregulation reduces payload binding and efficacy. Enzymatic inactivation of the payload	Develop novel payloads with unique mechanisms of action to bypass pre-existing resistance. Combine ADCs with targeted agents (e.g., PARP inhibitors for DDR). Engineer ADCs with dual, synergistic payloads	Alrhmoun and Sennikov[32]; Chen et al[131]; Ceci et al[133]

HER2: Human epidermal growth factor receptor 2; ADC: Antibody-drug conjugate; DDR: DNA damage response; pH: Potential of hydrogen; PARP: Poly-adenosine diphosphate ribose polymerase.