Two-photon photodynamic induction of PANoptosis and immunogenic cell death for precision tumor eradication using a dual-organelle-targeted STING agonist.

Abstract

Triple-negative breast cancer (TNBC) remains a formidable clinical challenge owing to its aggressive metastatic behavior and the absence of well-defined therapeutic molecular targets. Although photodynamic therapy (PDT) holds immense promise, its efficacy is often limited by the aggregation-caused quenching (ACQ) of conventional photosensitizers and the restricted tissue penetration of visible excitation light. To address these limitations, we developed DBC, an AIE-active photosensitizer featuring a highly twisted, sterically hindered molecular architecture. This structural design endows DBC with an exceptionally large two-photon absorption (TPA) cross-section, enabling high-contrast deep-tissue imaging and efficient phototherapy under near-infrared (NIR) excitation. Consequently, DBC efficiently generates reactive oxygen species (ROS) through both Type I and Type II photochemical pathways, ensuring potent photodynamic activity under diverse microenvironmental conditions. Mechanistically, DBC preferentially localizes to the ER and mitochondria. Upon light irradiation, the localized ROS burst induces severe organelle stress and synergistically triggers PANoptosis, a hybrid programmed cell death pathway integrating apoptosis, necroptosis, and pyroptosis. Concurrently, mitochondrial damage and ER stress promote mitochondrial DNA leakage and immunogenic cell death (ICD), leading to the activation of the cGAS-STING innate immune signaling pathway. The resulting production of type I interferons and pro-inflammatory cytokines remodels the tumor microenvironment by converting immunologically "cold" tumors into "hot" tumors, thereby enhancing antitumor immune activation. Collectively, the coordinated induction of PANoptosis, ICD, and cGAS-STING signaling establishes a self-reinforcing antitumor immune response, ultimately eliciting robust local tumor eradication and systemic therapeutic efficacy against TNBC. STATEMENT OF SIGNIFICANCE: This study addresses triple-negative breast cancer (TNBC) treatment by developing a photosensitizer, DBC, with a multiple-twist molecular architecture. Unlike traditional agents limited by shallow light penetration and quenching aggregation, DBC features exceptional near-infrared two-photon absorption for precise, deep-tissue photodynamic therapy. Mechanistically, it targeted both the endoplasmic reticulum and mitochondria to trigger PANoptosis, a coordinated programmed cell death mode. Furthermore, DBC acts as a cGAS-STING agonist to remodel the tumor microenvironment, effectively converting "cold" tumors into "hot" immunogenic ones. These findings bridge photophysical molecular design with advanced tumor immunotherapy, offering broader readers an impactful paradigm for engineering multi-functional biomaterials to combat aggressive cancers.