Immunotherapies that enhance cytotoxic lymphocyte activity against tumour cells have revolutionised modern cancer treatment. A limitation to these approaches is that the number and functionality of lymphocytes can vary significantly within tumors, leading to variation in the proportion of patients who respond positively to immunotherapy. Furthermore, intrinsic or acquired genetic mutations can determine the sensitivity or resistance of tumours to immunotherapy approaches such as checkpoint blockade and adoptive cell therapy. Here, we have applied CRISPR-based genetic screening approaches to uncover mechanisms of tumor immune evasion. Our results highlight a role for TNF-mediated bystander killing as a potent cytotoxic lymphocyte effector mechanism that can be enhanced by a class of drugs, called smac-mimetics, that sensitise tumour cells to TNF-induced cell death. The data generated has also identified new genes and pathways that may predict response to checkpoint blockade or be therapeutically targeted to improve the number of patients that benefit from immunotherapy.