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Gemcitabine (GEM), as a first‐line chemotherapeutics for pancreatic ductal adenocarcinoma (PDAC) treatment, still faces several clinical challenges, restricted by instability in blood circulations, low tumor selectivity, and acquired nature characteristics of chemo‐resistance. To solve these challenges, the rational design of combination therapy with GEM and other therapy modalities is imperative. Herein, a small molecular self‐assembly nano‐prodrug is developed, which can achieve the co‐delivery of GEM, Ferrocene and nutlin‐3a on the achievement of GEM‐induced apoptosis with ferroptosis. In this nano‐prodrug, the disulfide linkage not only acts as a GSH‐responsive trigger but also plays an important role in self‐assembly behavior of nanoparticle that can load nutlin‐3a. Interestingly, nutlin‐3a plays an important role in both ferroptosis and apoptosis, one is effectively sensitized cells to ferroptosis by inhibiting cystine uptake, and the other is promoted apoptosis by elevating p53 expression. To further enhance the drug tumor accumulation and maintain stability in systemic circulations, this nano‐prodrug is then encapsulated into plectin1 receptor‐targeting phospholipid micelles (DSPE‐PEG‐PTP), which displays high selective tumor inhibition and good biosafety on different mice models, especially in orthotopic and patient‐derived xenograft (PDX) models. The findings provide new insights into the combination therapy of GEM with ferroptosis for reduced chemo‐resistance on PDAC treatment. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma rapidly acquires resistance to chemotherapy, remaining a fatal disease. Immunotherapy is one of the breakthroughs in cancer treatment, which includes immune checkpoint inhibitors, chimeric antigen receptor T‐cell immunotherapy, and neoantigen vaccines. However, immunotherapy has not achieved satisfactory results in the treatment of pancreatic cancer. Immunogenic death comprises proinflammatory cell death, which provides a way to enhance tumor immunogenicity and promote an immune response in solid tumors. Herein, an ionic liquid ablation agent (LAA), synthesized from choline and geranic acid, which triggers necrosis‐induced immunotherapy by remodeling an immunosuppressive "cold" tumor to an immune activated "hot" tumor is described. The results indicate that LAA‐treated tumor cells can enhance immunogenicity, inducing dendritic cell maturation, macrophage M1 polarization, and cytotoxic T lymphocyte infiltration. The results of the present study provide a novel strategy for solid tumor immunotherapy. [ABSTRACT FROM AUTHOR]