Enhancing the photodynamic efficacy of hypericin in antitumor treatment by inhibiting the cell integration stress response

Photodynamic therapy (PDT) is a minimally invasive treatment technique that combines photosensitizers and light and can selectively exert cytotoxic effects on malignant tumor cells and prevent their metastasis. However, while PDT is effective, it also triggers a tumor cell integrated stress response (ISR) to produce cytoprotective stress granules (SGs), decreasing its therapeutic efficacy. In this study, we designed a nanodrug delivery system capable of inhibiting the ISR to enhance the antitumor effect of PDT. Specifically, the low-toxicity photosensitizer hypericin (HY) and the highly effective SGs inhibitor imatinib (IM) were encapsulated in the HY and IM nanoparticles (HINPs). HY converts oxygen into reactive oxygen species under light conditions, inducing the apoptosis of tumor cells but simultaneously induces the formation of SGs through the eukaryotic initiation factor-2α-dependent pathway, reducing tumor sensitivity to PDT. IM tightly binds to the SGs core protein Ras-GAP SH3 domain binding protein 1 (G3BP1), preventing G3BP1 from forming a complex with ubiquitin-associated protein 2-like protein to inhibit SGs formation; it also inhibits the ATF3/CHOP/GADD34/PP1 negative feedback regulatory signaling axis of ISR, further disrupting tumor cell ISR and enhancing the efficacy of HY PDT. Both in vivo and in vitro experiments confirmed that HINPs have potent antitumor activity, providing a way to improve the antitumor efficacy of PDT.