CRISPRa screen unveils noncanonical NF-κB to boost the antitumor activity of TCR-based CAR-T cells.

Overexpression of p52 enhances persistence, effector functions, and tumor control of TCR-based T cells by activating noncanonical NF-κB signaling.

• Why it matters: Limited T-cell persistence hampers the effectiveness of adoptive cancer therapies, especially in TCR-based treatments, necessitating new strategies to improve durability and response.
• What they did: An in vivo CRISPRa screen in STAR-T cells identified RELB as a key regulator, and subsequent overexpression of p52, RELB’s transcription partner, was tested for its ability to sustain T-cell activity under prolonged antigen exposure.
• The result: p52 overexpression promoted T-cell proliferation, effector functions, and tumor infiltration, while also providing partial resistance to checkpoint suppression, suggesting a promising approach to enhance TCR-based immunotherapy in solid tumors.