Despite significant success in some cancer patients, the majority do not benefit from immunotherapy. Since unleashing cytotoxic T lymphocyte (CTL) cytotoxicity is a major strategy of cancer immunotherapy, understanding how tumor cells evade CTL mediated killing is the next step for overcoming resistance. Previously, functional genomics, in particular Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) knockout (KO) screens, were used to identify tumor resistance mechanisms. Nevertheless, this approach only detects genes already expressed in tumor cells and may miss not expressed genes. Thus, this study focused on establishing a complementary CRISPR KO and CRISPR activation (CRISPRa) screen platform to comprehensively reveal tumor genetic circuits controlling CTL mediated killing. Analysis of screen control conditions confirmed effective gene editing and activation of gene expression across the whole genome. The CRISPRa and CRISPR KO screens identified 187 and 704 gene hits, respectively, including 60 shared hits. Best ranking gene hits validated previously identified genes involved in regulating CTL effector function including JAK1, JAK2, IFNGR1, STAT1, CASP8 and PTPN2. ILKAP, a gene previously unknown to play a role in tumor evasion, mediates tumor resistance to antigen specific T cell mediated killing independently from regulating antigen presentation, IFN-γ or TNF-α responsiveness. Moreover, ICAM1 was a top scoring complementary gene hit. The lack of membrane-bound ICAM-1 as well as the overexpression soluble ICAM-1 induce tumor resistance to CTL mediated killing.