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

Hengji Zhan, Hongjin Wang, Bolin Pan, Junlin Lu, Kanghua Xiao, Jiajian Lai, Zehua Chen, Kaiwen Jie, Siting Chen, Hong Li, Tianxin Lin () and Xu Chen ()
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Hengji Zhan: Sun Yat-sen University
Hongjin Wang: Sun Yat-sen University
Bolin Pan: Sun Yat-sen University
Junlin Lu: Sun Yat-sen University
Kanghua Xiao: Sun Yat-sen University
Jiajian Lai: Sun Yat-sen University
Zehua Chen: Sun Yat-sen University
Kaiwen Jie: Sun Yat-sen University
Siting Chen: Sun Yat-sen University
Hong Li: Guangzhou Jingke Biotech Group
Tianxin Lin: Sun Yat-sen University
Xu Chen: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63377-3

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