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

• Published in: iScience 2022-11, Vol.25 (11), p.105426-105426, Article 105426
• Main Authors: Le, Yi, Gao, Hong, Zhu, Angie, Felt, Kristen, Rodig, Scott, Bleday, Ronald, Zhu, Zhenglun
• Format: Article
• Language: English
• Subjects: Cancer; Cell biology; Immunology; Molecular biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.105426

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 in vivo 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. [Display omitted] •A TIME-EMS model to explore the mechanisms of chemotherapy•NF-κB mediates doxorubicin induction of VentX expression in TAMs•VentX-regulated TAMs promote tumor chemosensitivity >10-fold•A cell-death-independent immune mechanism for mediating chemotherapeutic effects Molecular biology; Immunology; Cell biology; Cancer