A Poly‐prodrug Nanosphere for Modulating Janus‐faced Nature of Pyroptosis to Launch an Immune Offensive and Defensive Warfare Reigniting the Cancer‐immunity Cycle

Abstract Pyroptosis provides a novel perspective for the design of anti‐tumor strategies. However, when pyroptosis reaches a plateau, its negative role becomes “defense” signaling to evade immune surveillance. Herein, a triblock polymeric micelles TPT@PIO NPs are reported, including a hydrophobic block backbone poly (propylene sulfide) (PPS), a hydrophobic side chain disulfide bond‐bearing indomethacin (MABHD‐IND), a hydrophilic block poly(ethylene glycol) methyl ether methacrylate (OEGMA), and an encapsulated hydrophobic drug topotecan (TPT) through hydrophobic forces, exhibit excellent stability and responsiveness to the oxidation‐reduction microenvironment. This dual treatment mode utilizes TPT to trigger the activation of the pyroptosis process and uses IND to eliminate the immune escape by inhibiting the COX‐2/PGE 2 pathway, ultimately making the growth of tumors being inhibited via the synergy of chemotherapy and immunotherapy. Furthermore, the failure of the immunosuppressive network accelerates the infiltration of CD8 + T cells into the lungs and impedes the generation of tumor nodules. The changes in levels of cytokines caused by pyroptosis and the immune memory effect enhance the defense of transfer as well. In general, the ability of TPT@PIO NPs to regulate the Janus‐faced nature of pyroptosis acts as an indispensable role in suppressing tumor proliferation and metastasis.