MMAE-Based Peptide–Drug Conjugates Targeting GPC3 for Precision Chemoradiotherapy in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), the third leading cause of cancer mortality, lacks effective therapies. Current chemoradiotherapy faces challenges from systemic toxicity and radiation side effects. We developed a series of GPC3-targeting peptide-drug conjugates (PDCs) integrating monomethyl auristatin E (MMAE) to enhance tumor-specific delivery. Among them, PDC 22 demonstrated efficient tumor cell internalization, drug release, G2/M cell cycle arrest (the most radiosensitive phase), and induced immunogenic cell death of GPC3-positive tumor cells. Mechanistically, PDC 22 reduced clonogenic survival by increasing γH2AX foci formation, activating DNA damage repair, and blocking cell progression. In xenograft models, PDC 22 specifically accumulates in tumor regions and significantly delays tumor growth with minimal toxicity. Notably, combining PDC 22 with radiotherapy resulted in superior tumor control compared with monotherapy, highlighting its potential for precision chemoradiotherapy in HCC. Thus, leveraging GPC3-targeting PDC technology for auristatin delivery with radiotherapy presents a promising therapeutic strategy for HCC.