Gene editing boosts immunotherapy

NK cells have been modified with CARs to improve tumour specificity, persistence and infiltration. CRISPR-Cas9 is used to disrupt inhibitory genes like KLRC1 (NKG2A), TGFBR2, CISH, and CD38, enhancing cytotoxicity and metabolic fitness. Incorporating IL-15 or IL-21 supports NK cell expansion and function. CAR designs targeting surface antigens and intracellular neoepitopes (via TCR-mimetic constructs) are broadening applications. Memory-like NK cells offer enhanced antitumour response and longer in vivo persistence, while allogeneic and iPSC-derived NK cells are under clinical evaluation.

Macrophages are sometimes engineered with CARs and cytokines to reprogram their typically suppressive roles in the tumour microenvironment. CRISPR screening has guided modifications to sustain proinflammatory states (e.g., ACOD1 knockout) and block immune checkpoints (e.g., SIGLEC5, SIRPα). Early trials of HER2- and mesothelin-specific CAR-M therapies have shown safety and initial signs of efficacy.

γδ T cells, which blend innate and adaptive traits, are under investigation for CAR-based therapy due to their stress-sensing TCRs and cytotoxic capabilities. Clinical trials are assessing allogeneic and engineered γδ T cells across various tumour types.

The study was led by researchers at Dana-Farber Cancer Institute and Zhejiang University, and it was published yesterday in Nature Biotechnology.