Mechanisms of resistance to antibody-drug conjugates in cancer: molecular barriers and pharmacological solutions

Antibody-drug conjugates (ADCs) are a potential category of specialized cancer therapeutics that integrate monoclonal antibodies (mAbs) with cytotoxic drugs. These therapies seek to provide very effective pharmaceuticals directly to neoplastic cells, enhancing the therapeutic index compared to traditional chemotherapy. Despite their clinical success, ADCs face significant challenges, particularly in the form of resistance mechanisms that limit their effectiveness. Resistance can arise through various pathways, including antigen-related alterations, impaired drug internalization, and inefficient payload release. Other factors that complicate ADC penetration and efficacy are tumor microenvironment factors, including hypoxia and acidic pH. This review discusses the mechanistic origin of ADC resistance, and investigates the major biological, chemical, and pharmacokinetic variables related to treatment failure. We also indicate the new approaches to fighting resistance, such as next-generation ADCs designs, drug combination therapies, and tumor microenvironment modulation. Lastly, we talk about the possibility of new payloads, better linkers, and other possible drug delivery systems that could further the ADC efficacy to combat cancer.