Reprogramming the tumor microenvironment with c-MYC-based gene circuit platform to enhance specific cancer immunotherapy

作者：Hengji Zhan, Hongjin Wang, Bailin Pan, Junlin Lu, Kanghua Xiao, Jiajian Lai, Zehua Chen, Kaiwen Jie, Siting Chen, Hong Li, Tianxin Lin, Xu Chen · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-63377-3 · 被引用次数：13 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Virus-based gene therapy research

Intratumor heterogeneity (ITH) is associated with anti-tumoral immune response and with the efficiency of cancer immunotherapy, yet overcoming ITH remains a significant challenge. Notably, cellular MYC (c-MYC) has been shown to be a pivotal orchestrator of this ITH progression. Here, we develop a c-MYC-based sensing circuit (cMSC) that is activated exclusively by aberrant c-MYC levels, along with an exosome-based cell-to-cell (CtC) system that augments communication among tumor cells, effectively targeting all cells in tumors circumventing the limitations imposed by ITH. Further expression of multifunctional immunostimulatory agents in these cMSC-reprogrammed cancer cells remodels the tumor microenvironment, enhancing selective T-cell-mediated oncolysis. Our cMSC/CtC platform specifically senses aberrant c-MYC expression and subsequently triggers a robust cancer immunotherapeutic response. These findings offer a promising avenue for targeting cancers via precisely sensing c-MYC, overcoming the limitations of ITH. Targeting tumors with c-MYC dysregulation is very challenging due to low MYC expression and intratumor heterogeneity. Here, the authors report a MYC-based gene circuitry that enhances immunotherapy response and tumor killing in bladder cancer.