A Minireview on Nanosized Hypericin-Based Inducer of Immune Cell Death Under ROS-Based Therapies

Immunotherapy is emerging as a powerful strategy against cancer; however, its efficacy is often blunted by the immunosuppressive tumor microenvironment (TME). Immunogenic cell death (ICD) can tilt this balance by releasing tumor-associated antigens and damage-associated molecular patterns that enhance TME immunogenicity, promote antigen-presenting cell maturation, and activate effector T cells. Ionizing radiation and doxorubicin (Dox) are two types of the common ICD inducers. However, they have severe off-target toxicities and limited therapeutic indices. To overcome these challenges, safe and natural products are now drawing widespread attention. Hypericin, a naturally occurring photosensitizer derived from the traditional Chinese herb Hypericum perforatum (St. John's wort), has been used medicinally for centuries, and is now recognized for its potent antimicrobial, antiviral, anti-inflammatory, and anticancer properties. Recent studies have revealed that hypericin can modulate tumor immunity, and when employed in photodynamic therapy (PDT) or sonodynamic therapy (SDT) it generates reactive oxygen species that trigger endoplasmic reticulum stress-mediated ICD. Nanocarrier-mediated delivery further amplified these effects by enhancing hypericin solubility, tumor accumulation, and ROS yield upon light irradiation. This minireview synthesizes the current knowledge on the immunomodulatory actions of hypericin within the tumor microenvironment, evaluates its performance as a PDT/SDT-based ICD inducer, and highlights that nanosized formulations of hypericin may accelerate the development of novel ICD inducers and immunomodulators.