CRISPR screens define unified hallmarks of cancer cell-autonomous immune evasion

Cancer immunotherapy has transformed cancer treatment, yet only a minority of patients achieve durable benefit. Although early efforts to enhance immunotherapy focused on boosting immune effector function, reversing T cell exhaustion, or altering the tumor microenvironment, it is now clear that cancer cell-autonomous mechanisms play a major role in immune escape. Such programs, driven by the cancer cell genome, transcriptome, and epigenome, include desensitization to cytokine signaling, such as interferon (IFN)γ and tumor necrosis factor (TNF); impaired antigen presentation; upregulation of suppressive ligands such as programmed cell death ligand 1 (PD-L1); and epigenetic silencing of immunogenic pathways. The rise of high-throughput functional genomics, especially in vitro and in vivo CRISPR-based screening, has greatly expanded our ability to map these pathways and define how tumors evade CD8⁺ T cell-mediated pressure. A deeper understanding of these cancer cell-autonomous immune-evasion mechanisms will be essential for developing new therapeutic strategies that broaden the impact of immunotherapy across diverse cancers.