Selective Induction of Cancer Cell Pyroptosis by Erbium Nanotuner Enhances Potent Anti‐Cancer Immunity

Pyroptosis, an immunogenic programmed cell death, is a robust way to activate anti-cancer immunity. However, it is very challenging to induce pyroptosis in cancer cells while sparing normal cells selectively. Herein, an Er³⁺-containing nanoparticle is screened from the whole series of lanthanides for boosting pancreatic cancer immunotherapy by selectively inducing cancer cell pyroptosis. To elicit tumor-specific inflammatory cell death, a tumor-targeting nanoplatform, termed the Erbium-RSL3 Inflammasome-Activating System (ERIS), was designed, invoking the "Greek goddess of discord" to unleash discord within tumors. ERIS has been proven to induce pyroptosis through lysosomal rupture, facilitated by a strong interaction between Er³⁺ and lysosomal phospholipid membranes, as evidenced by a 3.2-fold increase in GSDMD-N cleavage and a 12.2-fold increase in lactate dehydrogenase (LDH) release compared with controls. This localized inflammatory assault subverts tumor growth and promotes anti-cancer immune responses. Therefore, ERIS demonstrates remarkable tumor suppression with minimal systemic side effects across different pancreatic cancer models, achieved through pyroptosis-induced immune activation and remodeling of the immunosuppressive tumor microenvironments. This study identifies Er³⁺-based nanomedicine as a new class of cell-selective pyroptosis nanotuner, offering a unique opportunity to enhance the efficacy of cancer immunotherapies.