Hypertemperature‐Detonated Biomimetic Semiconductor Stromal Bombs for Enhanced Immunotherapy in Pancreatic Cancer

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is characterized by “copper avidity”, which easily leads to the dysregulation of copper ion homeostasis. It is possible to develop targeted nanodrugs that selectively kill cancer cells via cuproptosis. However, the dense stroma of PDAC acts as an airtight wall, which not only limits the penetration and distribution of therapeutic agents but also promotes immunosuppressive mechanisms via its hypoxia‐promoting effects, often leading to treatment failure. Thus, we developed a near‐infrared (NIR)‐responsive semiconductor polymer‐metal‒organic framework (MOF) nanoreactor (SPNMCH) that was loaded with copper sulfide nanoclusters (CuS x NCs) and hyaluronidase (HAase). This biomimetic semiconductor “bomb” extensively demolishes the wall (by highly activating HAase) and precisely eliminates tumor cells (through its active copper uptake to induce cuproptosis). Simultaneously, the synergistic effects of increased oxygen delivery and cuproptosis elicit robust antitumor immune responses to inhibit tumor progression and distant metastasis, and strong immune memory effects as observed in four mouse cancer models. Additionally, SPNMCH can be combined with anti‐programmed death receptor 1 (PD‐1) antibodies to further promote T cell‐mediated antitumor immunity. This study reveals a promising strategy for establishing a “hot” tumor immune niche in PDAC to promote the response to immunotherapy.