Biological ageing is accompanied by a decline in immune surveillance, including impaired CD8+ T cell function, which limits antitumour immunity and responses to immune checkpoint blockade therapies. However, the molecular mechanisms that limit the proliferation, persistence and sustained effector function of CD8+ T cells in the tumour microenvironment (TME) with age remain poorly defined.

In this preprint (not peer reviewed), Chen et al. use an in vivo single-cell CRISPR screening platform to identify genetic regulators that impair CD8+ T cell function with age during tumour progression. They transduced Cas9-expressing, ovalbumin (OVA)-reactive, naive OT-1 CD8+ T cells with a lentiviral CRISPR library targeting 60 transcriptional regulators and nuclear proteins. Transduced cells were adoptively transferred into young and aged mice one day before B16-OVA tumour implantation. OT-1 T cells were isolated from tumours 15 days later and profiled by Perturb-seq. Notably, loss of Dusp5 or Zfp219 selectively enriched for effector-like T cell states, which suggests that these genetic regulators promote dysfunctional programmes that restrict effector differentiation and proliferation.