NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations.

Limited therapeutic efficacy and severe side effects represent the central hurdles facing cancer chemotherapy. Immune suppression within tumor immune microenvironments (TIME) has been implicated in chemoresistance. In this study, using a TIME-enabling model system (TIME-EMS), we demonstrate that the chemotherapeutic agent doxorubicin has cytocidal effects on tumor cells at high dosage but induces changes in the immune landscape of the TIME at low noncytotoxic concentrations via NF-κB-mediated induction of homeobox protein VentX expression in tumor-associated macrophages (TAMs). We demonstrated that VentX-regulated TAMs drastically promote tumor chemosensitivity >10-fold but exert little effect on chemotoxicity to normal cells through activating cytotoxic T lymphocytes in a tumor-specific manner. Supported by the synergy of VentX-regulated TAMs and low-dosage noncytotoxic doxorubicin, our data suggest a cell-death-independent immune mechanism for improving the therapeutic index of chemotherapeutic agents.