Manipulating Offense and Defense Signaling to Fight Cold Tumors with Carrier‐Free Nanoassembly of Fluorinated Prodrug and siRNA

Abstract Chemoimmunotherapy has shown great potential to activate an immune response, but the immunosuppressive microenvironment associated with T cell exhaustion remains a challenge in cancer therapy. The proper immune‐modulatory strategy to provoke a robust immune response is to simultaneously regulate T‐cell exhaustion and infiltration. Here, a new kind of carrier‐free nanoparticle is developed to simultaneously deliver chemotherapeutic drug (doxorubicin, DOX), cytolytic peptide (melittin, MPI), and anti‐TOX small interfering RNA (thymocyte selection‐associated high mobility group box protein, TOX) using a fluorinated prodrug strategy. In this way, the enhanced immunogenic cell death (ICD) induced by the combination of DOX and MPI can act as “offense” signaling to increase CD8⁺ T‐cell infiltration, while the decreased TOX expression interfered with siTOX can serve as “defense” signaling to mitigate CD8⁺ T‐cell exhaustion. As a result, the integration of DOX, MPI, and siTOX in such a bifunctional system produced a potent antitumor immune response in liver cancer and metastasis, making it a promising delivery platform and effective strategy for converting “cold” tumors into “hot” ones.