Research on precision treatment of pancreatic cancer targeted by antibody-drug conjugates

Abstract

Pancreatic cancer, and especially pancreatic ductal adenocarcinoma (PDAC), is extremely difficult to treat due to early asymptomatic stage, molecular heterogeneity, and resistance to conventional treatments, with a 5-year survival rate of less than 10%. Antibody-drug conjugates (ADCs), as an emerging precision therapy, show the potential to treat PDAC through the synergy of antibody targeting and cytotoxic drugs. Multiple targets (such as uPAR, Mesothelin, CLDN18.2, and TROP2) are highly expressed in PDAC, which has become the key direction of ADC development. However, the matrix barrier restricts drug delivery, heterogeneous expression leads to efficacy differentiation, and drug resistance mechanisms further limit the role of ADCs. To overcome these challenges, researchers are exploring high-stability single domain antibodies, more potent payloads and linkers, bystander effect mechanisms, and combined treatment strategies with immune, autophagy, DNA damage repair, and other pathways. Bispecific ADC, conditionally activated ADC, and penetration enhancement design have also been used to improve efficacy. On the whole, ADCs offer hope for the treatment of PDAC. Future research and development should focus on improving delivery efficiency, alleviating drug resistance, and individualized design.