Light‐Triggered In Situ Gelation to Enable Robust Photodynamic‐Immunotherapy by Repeated Stimulations

TLDR

Photodynamic therapy can elicit systemic antitumor immunity, yet hypoxic tumor environments and weak conventional responses limit its efficacy against metastatic disease. The authors aim to create a light‑triggered in‑situ gelation platform that incorporates photosensitizer‑modified catalase and immune‑adjuvant nanoparticles to provoke robust antitumor immunity following PDT. By locally injecting a precursor mixture of PEGDA, photosensitizer‑modified catalase, and immune‑adjuvant nanoparticles into tumors and illuminating it, PEGDA polymerization forms a hydrogel that retains therapeutic agents and alleviates hypoxia. The resulting hydrogel permits multiple rounds of PDT, producing markedly stronger immune responses, an abscopal effect, and durable memory when combined with anti‑CTLA‑4 blockade, thereby markedly improving photoimmunotherapy from a single injection.

Abstract

Photodynamic therapy (PDT) has shown the potential of triggering systemic antitumor immune responses. However, while the oxygen-deficient hypoxic tumor microenvironment is a factor that limits the PDT efficacy, the immune responses after conventional PDT usually are not strong enough to eliminate metastatic tumors. Herein, a light-triggered in situ gelation system containing photosensitizer-modified catalase together with poly(ethylene glycol) double acrylate (PEGDA) as the polymeric matrix is designed. Immune adjuvant nanoparticles are further introduced into this system to trigger robust antitumor immune responses after PDT. Following local injection of the mixed precursor solution into tumors and the subsequent light exposure, polymerization of PEGDA can be initiated to induce in situ gelation. Such hybrid hydrogel with long-term tumor retention of various agents and the ability to enable persistent tumor hypoxia relief can enable multiple rounds of PDT, which results in significantly enhanced immune responses by multiround stimulation. Further combination of such gel-based multiround PDT with anticytotoxic T-lymphocyte antigen-4 checkpoint blockade offers not only the abscopal effect to inhibit growth of distant tumors but also effective long-term immune memory protection from rechallenged tumors. Therefore, such a light-triggered in situ gelation system by a single-dose injection can enable greatly enhanced photoimmunotherapy by means of repeated stimulations.