Utilizing Rationally Designed Photosensitizers to Drive Divergent Immunogenic Cell Death in Photoimmunotherapy

ABSTRACT

Photodynamic therapy (PDT)‐based photoimmunotherapy represents a promising modality for cancer treatment, combining the precision of PDT with the sustained efficacy of immunotherapy. A key innovation in this field involves the use of organic photosensitizers to induce immunogenic pyroptosis. However, the fundamental question of whether type I and type II PDT elicit equally potent immune responses remains unresolved. To address this, we developed a series of A‐D‐A structured organic photosensitizers via rational donor–acceptor engineering. This molecular strategy enables precise control over the photodynamic pathway by fine‐tuning the intramolecular charge transfer strength, thereby establishing a platform for systematically comparing their immunogenic potential. Our mechanistic investigations reveal a critical distinction: type I‐dominant photosensitizers are more effective than their type II‐dominant counterparts at triggering caspase‐1‐mediated pyroptosis. This pyroptotic cascade stimulates the release of damage‐associated molecular patterns and pro‐inflammatory factors, culminating in potent immune activation. As a result, the leading type I photosensitizer is more capable of inducing a systemic antitumor immune response and suppressing distant tumors under a low‐power 808 nm photoirradiation. Overall, this work not only decouples the immunogenic roles of type I and type II photodynamics but also provides a rational design strategy for advanced photoimmunotherapy agents.