Advances in light-activated PROTACs and phototherapy-combined approaches for cancer treatment

Traditional proteolysis-targeting chimeras (PROTACs) have emerged as a powerful strategy in cancer therapy by selectively degrading tumor-associated proteins, thereby inhibiting tumor proliferation and metastasis. However, their clinical translation remains limited due to challenges such as off-target effects, low cellular uptake, and insufficient tumor penetration. To address these limitations, light-activated PROTACs have been developed by integrating the spatiotemporal precision of phototherapy with conventional PROTACs. The photo-switchable PROTACs and photocaged PROTACs allow precise activation in tumor tissues while minimizing toxicity to healthy cells. Light-activated PROTACs not only precisely control the release of PROTACs but also synergistically treat tumors in conjunction with phototherapy. These innovations significantly reduce off-target effects and enhance therapeutic specificity. Here, we outline the mechanisms of light-activated PROTACs systems and review therapeutic strategies that utilize light-activated PROTACs in conjunction with PROTAC for tumor treatment. These systems not only exert anti-tumor effects by stimulating reactive PROTAC, but their combination with phototherapy, which presents a promising approach that could overcome current limitations and may advance the clinical application of PROTAC-based cancer therapies.