Enhance Anti-Tumor Immunity by CD004-induced Reprogramming of IL-17-Producing CD8+ T Cells Toward Cytotoxic Tc1-Like Phenotypes 2237759

Abstract Introduction While IL-17-producing CD8+ T cells (Tc17) are conventionally considered tumor-promoting, recent studies have highlighted their functional plasticity. Tc17 cells can be reprogrammed into IFN-γ-producing, cytotoxic Tc1-like phenotype, offering new opportunities for their application in immunotherapy. Through database screening, this study investigates the potential of a candidate drug, CD004, to induce Tc17 reprogramming and enhance anti-tumor immunity. Methods Polarized Tc17 cells were treated with CD004, the compound identified from database screening with anti-inflammatory properties. The expression of IL-17A, IFN-γ, T-bet, Eomes, and granzyme B was analyzed by flow cytometry. Cytotoxicity was evaluated against E.G7-OVA lymphoma cells, and metabolic profiling was performed to explore underlying mechanisms. An adoptive transfer model using E.G7-OVA-bearing mice was employed to assess the in vivo anti-tumor efficacy. Results CD004 treatment significantly upregulated IFN-γ, T-bet, and granzyme B expression in Tc17 cells, accompanied by a reduction in IL-17A expression. Cytotoxicity assays confirmed enhanced tumor cell killing after treatment in vitro. Metabolic analysis suggested that Tc17 reprogramming may involve mitochondrial metabolic rewiring. In the in vivo model, adoptive transfer of CD004-treated Tc17 significantly reduced tumor volume compared with the control group. Conclusion CD004 treatment reprogrammed Tc17 cells toward a Tc1-like phenotype, enhancing their cytotoxicity and anti-tumor function both in vitro and in vivo. These findings highlight a potential therapeutic strategy for cancer immunotherapy through pharmacological modulation of T cell plasticity. Funding Source This study is partially supported by the National Science and Technology Council, Taiwan, and the Chinese Medicine Research Center of China Medical University, under the Featured Areas Research Center Program within the framework of the Higher Education S Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)