Non-muscle invasive bladder cancer, a disease with the oldest immunotherapeutic standard of care, has seen recent improvements in treatment via the application of checkpoint blocking antibodies. Unfortunately, response rates to programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) blocking antibodies remain low despite stratification by biomarkers. Sharing common biology with T cells but lacking true antigen-specificity and responding earlier to tumorigenic threats, natural killer (NK) cells present an ideal target for combination immunotherapies. NK-targeted immunotherapies under clinical investigation, including anti-NKG2A antibodies, interleukin agonists, and engineered viral vectors, hold promise in altering the immunotherapeutic landscape in bladder cancer and will be the focus of this review.
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