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

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.