| RRC ID |
89926
|
| Author |
Suh J, Yook G, Bae J, Jeong S, Kim S, Kim JH, Kang HG, Wu MR, Kim YJ, Kim JH.
|
| Title |
A logic-gated synthetic circuit coupled with microenvironmental reprogramming overcomes immune exclusion in antigen-poor chondrosarcoma.
|
| Journal |
Trends Biotechnol
|
| Abstract |
Chondrosarcoma remains refractory to immunotherapy due to a paucity of targetable antigens and a suppressive tumor microenvironment (TME). We developed a modular strategy integrating tumor-intrinsic genetic logic with rational TME reprogramming to overcome these barriers. Using a 57,715-element massively parallel reporter assay, we identified chondrosarcoma-selective synthetic promoters and engineered a Boolean AND-gate circuit that ensures high-fidelity expression of a surface T cell engager exclusively within malignant cells. To further address the immunosuppressive TME, we identified macrophage migration inhibitory factor (MIF) as a target for blockade. Single-cell RNA sequencing in human PBMC-reconstituted chondrosarcoma xenograft models revealed that the circuit initiates T cell activation, while MIF blockade prevents exhaustion by promoting proliferative T cells and M1-polarized macrophages. Local administration induced a systemic abscopal effect, regressing distant, untreated tumors. Collectively, these findings provide a programmable blueprint for converting immunologically cold, antigen-poor malignancies into systemically immune-responsive states.
|
| Published |
2026-9-7
|
| DOI |
10.1016/j.tibtech.2026.08.008
|
| PII |
S0167-7799(26)00343-4
|
| PMID |
42705947
|
| Resource |
| Human and Animal Cells |
HS-SY-II(RCB2231)
Yamato-SS(RCB3577)
Aska-SS(RCB3576) |
