A Dual‐Responsive STAT3 Inhibitor Nanoprodrug Combined with Oncolytic Virus Elicits Synergistic Antitumor Immune Responses by Igniting Pyroptosis

Abstract Immune checkpoint blockade (ICB) therapy shows excellent efficacy against malignancies; however, insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (TME) are considered as the two major stumbling blocks to a broad ICB response. Here, a combinational therapeutic strategy is reported, wherein TME‐reactive oxygen species/pH dual‐responsive signal transducers and activators of transcription 3 inhibitor nanoprodrugs MPNPs are combined with oncolytic herpes simplex virus 1 virotherapy to synergistically ignite pyroptosis for enhancing immunotherapy. MPNPs exhibit a certain level of tumor accumulation, reduce tumor cell stemness, and enhance antitumor immune responses. Furthermore, the simultaneous application of oncolytic viruses (OVs) confers MPNPs with higher tumor penetration capacity and remarkable gasdermin‐E‐mediated pyroptosis, thereby reshaping the TME and transforming “cold” tumors into “hot” ones. This “fire of immunity” strategy successfully activates robust T‐cell‐dependent antitumor responses, potentiating ICB effects against local recurrence and pulmonary metastasis in preclinical “cold” murine triple‐negative breast cancer and syngeneic oral cancer models. Collectively, this work may pave a new way and offer an unprecedented opportunity for the combination of OVs with nanomedicine for cancer immunotherapy.