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

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.