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

ABSTRACT 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 Er ³⁺ ‐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 Er ³⁺ 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 Er ³⁺ ‐based nanomedicine as a new class of cell‐selective pyroptosis nanotuner, offering a unique opportunity to enhance the efficacy of cancer immunotherapies.