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

Sep 23, 2026

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Intratumor heterogeneity (ITH) undermines anti-tumoral immunity and limits the efficacy of cancer immunotherapy, with c-MYC emerging as a key driver of ITH progression. A c-MYC-based sensing circuit (cMSC) is engineered to activate exclusively in response to aberrant c-MYC levels, paired with an exosome-based cell-to-cell communication system to coordinate tumor-wide targeting. Reprogrammed cancer cells further express multifunctional immunostimulatory agents, reshaping the tumor microenvironment to enhance selective T-cell mediated oncolysis and trigger robust immunotherapeutic response.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Introduction

Design of the cMSC and exosome-based CtC system

Tumor microenvironment remodeling and T-cell mediated oncolysis

Therapeutic implications and targeting strategy

Article [https://doi.org/10.1038/s41467-025-63377-3](https://doi.org/10.1038/s41467-025-63377-3) Reprogramming the tumor microenvironment with c-MYC-based gene circuit platform to enhance speciﬁc cancer immunotherapy Received: 19 December 2024 | Accepted: 18 August 2025 | | --- | | | | Check for updates | Hengji Zhan1,2,3,6, Hongjin Wang1,2,3,6, Bolin Pan1,2,3,6, Junlin Lu 1,2,3,6, Kanghua Xiao1,2,4,6, Jiajian Lai1,2,3, Zehua Chen1,2,3, Kaiwen Jie1,2,3, Siting Chen1,2,3, Hong Li5, Tianxin Lin 1,2,3 & Xu Chen 1,2,3 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. Immunotherapy has achieved great clinical success in many types of cancer, yet a large proportion of patients with cancer, especially those with solid tumors, do not beneﬁt from it. Moreover, the determinants of cancer immunotherapy efﬁcacy remain largely unknown1. A leading hypothesis in the immunotherapy ﬁeld is intratumor heterogeneity (ITH), manifested by a diverse distribution of clonal and subclonal mutations and neoantigens2,3, which may affect immune surveillance4–6. In addition, ITH is crucially involved in resistance to therapy, metastasis and cancer relapse, yet overcoming ITH is still a major challenge7–9. Although ITH is a complex biological process and difﬁcult to predict, some important factors, such as cellular MYC (c-MYC), change in expression as tumor cells progress through ITH, contributing to the diverse phenotypes observed within a tumor10. c-MYC is a highly heterogeneously expressed transcription factor that serves as a pivotal orchestrator of transcriptional and phenotypic diversity in cancer10,11. The overexpression of c-MYC, which serves as a central oncogene inmost tumors, leads to cancer progression and poor prognosis12–16. Many efforts have been devoted to interfering with c-MYC function 1Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. 2Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. 3Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, China. 4Guangdong Provincial Key Laboratory of Urology, Guangzhou Institute of Urology, Department of Urology, The First Afﬁliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China. 5BioMed Laboratory, Guangzhou Jingke Biotech Group, Guangzhou, China. 6These authors contributed equally: Hengji Zhan, Hongjin Wang, Bolin Pan, Junlin Lu, Kanghua Xiao. e-mail: [lintx@mail.sysu.edu.cn](lintx@mail.sysu.edu.cn); [chenx457@mail.sysu.edu.cn](chenx457@mail.sysu.edu.cn) directly in tumor cells17,18. However, simple inhibition of high c-MYCexpressing cells fails to kill all cancer cells due to the escape of low cMYC-expressing cells. In addition, indiscriminately inhibiting MYC transcriptional mechanisms by targeting cofactors such as MAX, CDKsand BRD4, USPs, or P

FAQs

Why is intratumor heterogeneity (ITH) a challenge for cancer immunotherapy?

ITH contributes to variable immune recognition and can limit immunotherapy efficacy, including through immune evasion and therapy resistance. Overcoming ITH remains a major challenge for clinical application.

What is the c-MYC-based sensing circuit (cMSC)?

The cMSC is activated exclusively by aberrant c-MYC levels, acting as a precise sensor for pathological c-MYC expression. It is designed to circumvent limitations created by ITH.

How does the exosome-based cell-to-cell (CtC) system help achieve tumor-wide targeting?

The CtC system augments communication among tumor cells, enabling coordination so that targeting can effectively cover all cells in tumors despite ITH-driven variability.

Sep 23, 2026

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