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.