Ferroptosis and Pyroptosis Co‐Activated Nanomodulator for “Cold” Tumor Immunotherapy and Lung Metastasis Inhibition

Abstract Immune checkpoint blockade (ICB) therapy is an emerging strategy for cancer immunotherapy; however, the actual effects of ICB therapy are greatly limited by the immunosuppressive tumor microenvironment (TME, i.e., “cold” tumors). Although engineered nanomaterials display significant importance to regulate TME in cancer treatment, most of them focus on “immunosilent” apoptotic processes that cannot elicit sufficient immune responses for further immunotherapy. Herein, a GSH‐responsive nanomodulator is reported that can reverse the immunosuppressive TME for “cold” tumor immunotherapy and lung metastasis inhibition through simultaneous ferroptosis and pyroptosis induction. The nanomodulator is constructed by loading FDA‐approved sulfasalazine (SAS) and doxorubicin (DOX) on disulfide‐doped organosilica hybrid micelles, where SAS and DOX are released through the GSH‐stimulated rupture of micelles to induce ferroptosis and pyroptosis, respectively, promoting dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) elevation through massive tumor‐associated antigen release. In vivo experimental results verify that desirable tumor destruction of the nanomodulator at low concentrations is achieved. More importantly, combination of this nanomodulator and programed death ligand‐1 antibodies significantly inhibits primary tumors and distant lung metastases as a result of elevated mature DCs and CTLs. This strategy to modulate immunosuppressive TME by nanomodulator‐induced non‐apoptotic death provides a new promising paradigm for ICB therapy.