Immunomodulatory‐Photodynamic Nanostimulators for Invoking Pyroptosis to Augment Tumor Immunotherapy

Abstract Cancer immunotherapy is restricted to immune resistance caused by immunosuppressive tumor microenvironment. Pyroptosis involved in antitumor immunotherapy as a new schedule is prospective to reverse immunosuppression. Herein, acidic tumor microenvironment (TME)‐evoked MRC nanoparticles (MRC NPs) co‐delivering immune agonist RGX‐104 and photosensitizer chlorine e6 (Ce6) are reported for pyroptosis‐mediated immunotherapy. RGX‐104 remodels TME by transcriptional activation of ApoE to regress myeloid‐derived suppressor cells' (MDSCs) activity, which neatly creates foreshadowing for intensifying pyroptosis. Considering Ce6‐triggered photodynamic therapy (PDT) can strengthen oxidative stress and organelles destruction to increase immunogenicity, immunomodulatory‐photodynamic MRC nanodrugs will implement an aforementioned two‐pronged strategy to enhance gasdermin E (GSDME)‐dependent pyroptosis. RNA‐seq analysis of MRC at the cellular level is introduced to first elucidate the intimate relationship between RGX‐104 acting on LXR/ApoE axis and pyroptosis, where RGX‐104 provides the prerequisite for pyroptosis participating in antitumor therapy. Briefly, MRC with favorable biocompatibility tackles the obstacle of hydrophobic drugs delivery, and becomes a powerful pyroptosis inducer to reinforce immune efficacy. MRC‐elicited pyroptosis in combination with anti‐PD‐1 blockade therapy boosts immune response in solid tumors, successfully arresting invasive metastasis and extending survival based on remarkable antitumor immunity. MRC may initiate a new window for immuno‐photo pyroptosis stimulators augmenting pyroptosis‐based immunotherapy.