While immune checkpoint inhibition therapies have revolutionized cancer treatment, response rates in many cancer types are still low. Unraveling the molecular mechanisms underlying immune cell activation upon antigen presentation and checkpoint inhibition can shed new light on how to further modulate and improve immune therapy. While protein coding genes have been studied extensively in this context, the role of lncRNAs remains largely elusive. By means of pooled CRISPR-interference screens in a newly developed and validated T-cell tumor cell co-culture model system, we aim to uncover lncRNA modulators of T-cell activation and checkpoint inhibition. Candidate lncRNAs will be extensively validated using lncRNA targeting antisense oligonucleotides in various in vitro and in vivo immune oncology models, and their mechanism of action will be studied using state-of-the art molecular techniques. This project will broaden our understanding of T-cell activation and will reveal novel candidate therapeutic lncRNA targets to boost checkpoint inhibition response.