Platinum Prodrug Nanoparticles with COX‐2 Inhibition Amplify Pyroptosis for Enhanced Chemotherapy and Immune Activation of Pancreatic Cancer

Abstract Pyroptosis, an emerging mechanism of programmed cell death, holds great potential to trigger a robust antitumor immune response. Platinum‐based chemotherapeutic agents can induce pyroptosis via caspase‐3 activation. However, these agents also enhance cyclooxygenase‐2 (COX‐2) expression in tumor tissues, leading to drug resistance and immune evasion in pancreatic cancer and significantly limiting the effectiveness of chemotherapy‐induced pyroptosis. Here, an amphiphilic polymer (denoted as PHDT‐Pt‐In) containing both indomethacin (In, a COX‐2 inhibitor) and platinum(IV) prodrug (Pt(IV)) is developed, which is responsive to glutathione (GSH). This polymer self‐assemble into nanoparticles (denoted as Pt‐In NP) that can disintegrate in cancer cells due to the GSH responsiveness, releasing In to inhibit the COX‐2 expression, hence overcoming the chemoresistance and amplifying cisplatin‐induced pyroptosis. In a pancreatic cancer mouse model, Pt‐In NP significantly inhibit tumor growth and elicit both innate and adaptive immune responses. Moreover, when combined with anti‐programmed death ligand (α‐PD‐L1) treatment, Pt‐In NP demonstrate the ability to completely suppress metastatic tumors, transforming “cold tumors” into “hot tumors”. Overall, the sustained release of Pt(IV) and In from Pt‐In NP amplifies platinum‐drug‐induced pyroptosis to elicit long‐term immune responses, hence presenting a generalizable strategy for pancreatic cancer.