Porphyrin-heptazine framework photosensitizers for hypoxia-tolerant pyroptotic photo-immunotherapy via enhanced radical production

Cellular pyroptosis as a potent immunogenic cell death mechanism offers a transformative approach for immunotherapy. However, the efficient pyroptosis of tumor cells induced by photodynamic therapy remains a great challenge, especially under hypoxic conditions. To address this issue, we rationally engineer covalent triazine/heptazine frameworks (CTFs/CHFs) by integrating porphyrin units as electron donors to create porphyrin-triazine (TPP-TRZ) and porphyrin-heptazine (TPP-HPT) photosensitizers that enhance oxygen-independent reactive oxygen species generation through improved intersystem crossing and reduced singlet-triplet energy gaps. The heptazine unit, owing to superior electron-accepting properties over the triazine unit, enables TPP-HPT to facilitate more efficient radical production (•OH and O₂^•−) under red light irradiation as compared to TPP-TRZ. TPP-HPT under light irradiation effectively triggers pyroptotic cell death, which is characterized by membrane disruption and inflammatory cytokine release, thereby further amplifying immunogenic cell death, reshaping the immunosuppressive tumor microenvironment, and enabling photo-immunotherapy. This work presents a novel strategy for designing metal-free, high-performance oxygen-independent photosensitizers for combating hypoxic tumors and eliciting systemic antitumor immunity.