Yale Medicine

High-Throughput Screening, CRISPR & Immunotherapy - The Sidi Chen Lab at Yale School of Medicine

The Sidi Chen laboratory at Yale School of Medicine is leveraging high‑throughput CRISPR screening to map every gene that influences immune‑cell behavior in cancer settings. By perturbing the full complement of ~20,000 human genes in vivo, the team seeks to pinpoint genetic levers that can be harnessed for next‑generation immunotherapies. The approach yields three distinct therapeutic pathways: first, using screen hits to discover novel targets that can be attacked with conventional modalities such as small‑molecule inhibitors or monoclonal antibodies; second, directly editing “undruggable” genes within patient‑derived cells to create engineered cellular therapeutics; and third, delivering the gene‑editing machinery systemically as a gene‑therapy platform that reprograms the immune system in situ. Chen emphasizes the “gene editing for, of, and as immunotherapy” paradigm, describing the shotgun, unbiased screens as a “shotgun approach” that narrows thousands of candidates to a manageable set of high‑impact genes. Examples include genes that modulate T‑cell exhaustion and checkpoints previously considered inaccessible to drug development. The implications are profound: biotech firms can accelerate target validation, reduce reliance on serendipitous discovery, and open therapeutic avenues for cancers resistant to existing checkpoint inhibitors. Ultimately, this strategy promises to expand the immunotherapy arsenal and shorten the timeline from gene discovery to clinical candidate.