Spatiotemporal control of CAR-T cell TNF release via tumor-targeted irradiation.

Local irradiation of human riTNF CAR-T cells drives high tumor necrosis factor (TNF) secretion and yields greater tumor regression than either riTNF CAR-T alone or irradiation alone in xenograft and murine models.

• Why it matters: Solid-tumor CAR-T efficacy is limited by poor infiltration and impaired effector function, while radiotherapy can fail due to radioresistance and metastatic spread; a way to localize inflammatory signaling is needed.
• What they did: Tumor-infiltrating T cells were profiled to identify radiation-responsive genes, and synthetic radioinducible promoters were engineered to control TNF expression in human CAR-T cells, producing irradiation-triggered TNF release independent of antigen engagement.
• The result: In human xenograft and murine tumor models, combining riTNF CAR-T cells with local irradiation increased intratumoral TNF (not systemic), tumor necrosis and apoptosis, vascular disruption, and CAR-T infiltration, enabling spatially and temporally controlled cytokine delivery.

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