Antigen spreading mediates heterogeneous solid tumor eradication by DNA demethylating agent–programmed CAR T cells
- Yelei Guo
- Chuan Tong
- Jianshu Wei
- Zhiqiang Wu
- Yuting Lu
- Fuxin Han
- Yipeng Zhang
- Chunmeng Wang
- Jinhong Shi
- Fengxia Shi
- Yao Wang
- Weidong Han
2026-05-12
Antigen heterogeneity substantially limits the efficacy of chimeric antigen receptor–modified T (CAR T) cell therapy against solid tumors. Our study highlights the potent antitumor activity of low-dose decitabine-primed CAR T (dCAR T) cells in solid tumor models, a benefit previously confirmed in hematologic malignancies. Notably, dCAR T cell infusion in immunocompetent mice led to substantial elimination of mixed tumor masses containing both antigen-positive and antigen-negative cells, without the need for prior lymphodepletion. Our analysis showed notable proinflammatory remodeling of the tumor immunosuppressive microenvironment. Crucially, antigen-activated dCAR T cells sustained high levels of interferon-γ production, which induced immunogenic cell death in tumor cells and activated conventional dendritic cells. This, in turn, stimulated endogenous CD8 + T cells, enhancing their antigen-spreading capacity and aiding in the clearance of abscopal antigen-negative tumors. These findings reveal the robust antigen-spreading capability of dCAR T cells, underscoring their clinical potential in addressing solid tumors with inherent antigen heterogeneity.