Enhancing anticancer efficacy while avoiding toxicity to normal tissues represents a critical scientific challenge in antitumor therapy. Developing drugs capable of selectively killing tumor cells is a key strategy to address this challenge [1].

Proteolysis Targeting Chimeras (PROTACs) align exceptionally well with this core requirement in both design philosophy and mechanism of action. Composed of a target protein ligand, a linker, and an E3 ubiquitin ligase ligand, PROTACs induce the ubiquitination and degradation of target proteins that are highly expressed, abnormally activated, or critical for tumor cell survival [2,3]. Currently, dozens of PROTACs have entered clinical trials [4]; however, most target proteins and E3 ubiquitin ligases are not exclusive to tumor cells, leading to off-target toxicity caused by degradation of target proteins in normal cells [5]. For example, BET-targeting PROTACs were found to inhibit BET proteins in normal tissues, triggering off-target toxicity, including lethargy, worsening skin conditions, reduced mobility, and spinal curvature [6]. Off-target toxicity remains one of the primary challenges facing the clinical application of PROTACs.

Photodegradation-Targeting Chimeras (PDTACs) offers a solution to this challenge. PDTACs consists of a target protein ligand, a linker, and a photosensitizer [7,8]. In 2022, Liu's team created the first PDTAC by linking the photosensitizer verteporfin (VPF) to a glutathione peroxidase 4 (GPX4)-targeting ligand. After the ligand binds to GPX4, light exposure at the lesion site induces VPF to generate reactive oxygen species (ROS), which degrade GPX4. By controlling the light exposure area, GPX4 degradation is confined to the lesion site, theoretically avoiding off-target toxicity [7]. However, in practical applications, the tumor boundary is difficult to define, and existing light exposure technologies struggle to precisely limit the illuminated area. This makes it challenging to confine light exposure strictly within the tumor boundaries, potentially damaging normal tissues adjacent to the tumor while killing cancer cells [9,10].

Von Hippel-Lindau (VHL) protein promotes tumorigenesis by regulating the p53 downstream pathway and enhancing CDK2/4 activation [[11], [12], [13]]. Based on this, this study designed a series of PDTACs drugs with different linkers. These drugs utilize monosubstituted zinc phthalocyanine (ZnPc-COOH) as the photosensitizer and VH032–NH2 as the VHL target protein ligand [14,15]. Among them, ZnPc-PEG2-VH032 was selected as the most effective in killing T24 cells after light exposure. This compound effectively degrades VHL upon illumination, exhibiting a photodynamic index (PI) of 36,397 (PIIC50-dark in tumor cell/IC50-light in tumor cell), which is 50 times higher than that of the clinically used phthalocyanine photosensitizer Photosens® (PI = 725) [16]. Further studies revealed that light-activated ZnPc-PEG2-VH032 exhibited significantly higher T24 cells (bladder cancer) killing capacity than SV-HUC-1 cells (normal cells), with a selectivity index (SI) of 749 (SIIC50-light in normal cell/IC50-light in tumor cell). This makes it the first PDTAC drug with high SI characteristics, and such a high SI is also extremely rare among photosensitizers. Mechanistic studies revealed that although VHL expression levels showed no significant difference between T24 cells and SV-HUC-1 cells, CDK2/4 activation was markedly higher in T24 cells than in SV-HUC-1 cells, indicating more active VHL regulation of CDK2/4 in T24 cells. Furthermore, T24 cells exhibited stronger uptake of ZnPc-PEG2-VH032 compared to SV-HUC-1 cells. These factors collectively contribute to the selective tumor cell killing efficacy of ZnPc-PEG2-VH032 (Scheme 1). In an in vivo orthotopic non-muscle-invasive bladder cancer (NMIBC) animal model, the therapeutic effect of ZnPc-PEG2-VH032 matched that of mitomycin C (MMC), a clinically used Class I chemotherapy drug for bladder cancer.