PPS03 triggers cancer-selective necroptosis in hepatocellular carcinoma via macropinocytosis-dependent ROS overload

Hepatocellular carcinoma (HCC) may be curable when detected and at an early stage. However, recurrence and metastatic progression occur frequently following therapeutic intervention, leading to treatment-refractory disease. Such refractory HCCs are resistant to systemic therapies, facilitating metastatic dissemination and disease relapse, highlighting the need for alternative therapeutic strategies. To address the limited efficacy of available systemic therapies, we developed a new polyaspartic acid (PASP) based polymer-metal complex, PPS03, with well-defined physicochemical properties, including nanoscale size distribution and stable metal incorporation. We showed that PPS03 induced cancer-selective necroptosis through preferential macropinocytic uptake in patient-derived metastatic HCC models. Specifically, PPS03 promoted necroptotic cell death by stimulating an accumulation of the mitochondrial reactive oxygen species (ROS) via selective intratumoral elevation of hydrogen peroxide (H 2 O 2 ). Mechanistically, PPS03 exploited differential macropinocytic activity, which is high in tumor cells but very low in normal hepatocytes. This activity enabled selective uptake of PPS03-bound selenomethionine and ferrous iron, amplifying H 2 O 2 -mediated mitochondrial ROS production within cancer cells. Consistent with this selectivity, PPS03 exhibited minimal cytotoxicity in normal THLE-2 hepatocytes, while it strongly suppressed the viability of HCC cells. Notably, in patient-derived cisplatin-resistant metastatic HCC models, PPS03 significantly inhibited tumor growth both in vitro and in vivo whereas cisplatin showed no significant efficacy. Furthermore, PPS03 reduced stem-like tumor features, as evidenced by decreased sphere formation and reduced CD133 expression, likely reflecting preferential elimination of stem-like tumor cells. Collectively, these findings present PPS03 as a polymer-metal complex that selectively induces necroptosis in refractory HCC with minimal off-target toxicity, providing a potential therapeutic strategy to address drug resistance in advanced disease.