Immune “checkpoint” inhibitors such as anti-PD1 represent the most significant advance in cancer treatment in the last 30 years and function by rejuvenating existing anti-tumour T lymphocyte responses. Effectiveness is limited to tumours with infiltrating tumor-specific cytotoxic T lymphocytes and resistance to checkpoint inhibition is common thus ~2000 clinical trials are evaluating the efficacy of checkpoint combination therapies to circumvent this. Natural killer (NK) cells are the innate equivalent to cytotoxic T lymphocytes, spontaneously detecting and killing transformed cells and contribute to cancer immune surveillance. A clear advantage of targeting NK over T cells in immunotherapy is NK cell function is not dependent on a specific tumour neoantigen, thus potentially all NK cells can be targeted to participate in the tumour immune response. Mature, functional NK cells are frequent in blood and lymphoid organs, yet cancer efficiently evades NK cell detection resulting in metastases in vital organs ultimately leading to death. Understanding the mechanisms of NK cell evasion evolved by tumour cells will lead to innovative immunotherapy strategies to impair tumour metastasis. We recently discovered of a potent intracellular checkpoint in NK cell activation, CIS which limits NK cell responsiveness to growth factors controlling their activity and homeostasis. Inhibition of CIS protects mice from tumour metastasis and impairs primary tumour growth. While the pharmacological modulation of this checkpoints is an obvious area for immunotherapeutic development, our data highlight that NK cell checkpoints are a major pathway by which cancer evades immune clearance and manifest in disease. This presentation will outline the potential for targeting NK cells in human cancer and the innovative CRISPR-Cas9 screens that exploit NK cell pressure on tumours and NK cell dependency on growth factors to identify checkpoint resistance mechanisms and novel pathways to enhance human NK cell function and recognition of transformed cells.