Pyrazolone-Modified Photosensitizers for Precise Cell Membrane Rupture to Enhance Cancer Immunotherapy

The advancement of immunotherapy aims to achieve complete tumor eradication. However, several critical challenges hinder the efficacy of conventional phototherapy-mediated immune responses, including insufficient immunogenicity and the presence of an immunosuppressive tumor microenvironment. Nonprogrammed cell death, as a highly immunogenic pathway, offers a promising strategy to enhance immune responses. Herein, a membrane-anchored photodynamic immunotherapy agent, PNBSe, was developed by conjugating a selenium-substituted benzophenothiazine photosensitizer with a pyrazolone group, enabling membrane targeting via pyrazolone-protein interactions. Upon light irradiation, PNBSe induced rapid and intense cell necrosis characterized by significant cell membrane rupture, organelle swelling, and content leakage. Further investigations demonstrated that PNBSe activated inflammatory signaling pathways, induced immunogenic cell death, and reshaped the immunosuppressive tumor microenvironment, ultimately promoting systemic antitumor immune responses in vivo. This membrane-anchored small molecule provides a novel perspective for promoting cancer photodynamic immunotherapy.