In vivo genome-wide CRISPR screens of human T cells in solid tumours.

In vivo CRISPR screens identified GNAS and P2RY8-Gα13 as key regulators of human T cell infiltration and dysfunction in solid tumours, improving immunotherapy efficacy.

• Why it matters: Understanding genetic factors that limit T cell performance in solid tumours is crucial for developing more effective therapies, as in vitro studies often miss in vivo regulatory mechanisms.
• What they did: Researchers developed an efficient in vivo model to recover human T cells from tumours and performed two genome-wide CRISPR knockout screens to identify regulators of T cell abundance and effector function, focusing on GNAS and P2RY8-Gα13.
• The result: Knocking out GNAS enhanced T cell resistance to suppressive signals and improved tumour control across models, while combined knockout with P2RY8-Gα13 further boosted therapeutic potency, enabling systematic genetic optimization of T cell therapies.