Natural Killer (NK) cells, long overshadowed by other immune cell–based immunotherapies, are emerging as potent anticancer effectors with distinct advantages and therapeutic challenges. NK cells act rapidly on cancer cells without prior sensitization, and by balancing between inhibitory and activating signals, they eliminate transformed cells in circulation and participate in early metastasis control. But most often, the tumour cells intelligently overcome it by inhibiting NK Cell activities or by forming protective clusters. NK cells on the other hand, act as “field commanders,” on solid tumours, attracting Conventional Dendritic Cells or cDC1 and cytotoxic T cells for tumour defence by releasing chemokines. But again, the tumour microenvironment imposes profound Tumour Growth Factor-Beta (TGF-β)-driven suppression and reprogramming of NK cells which make them disarmed or convert them to exhausted Type 1 Innate Lymphoid Cells (ILC1s) which by producing pro-inflammatory cytokines contribute to tumour progression. Therefore, the future immunotherapy aims to develop new immuno-therapeutic strategies to energize and boost NK cell activity in combination with widely acclaimed T cell based therapeutic methods. This is supposed to achieve through engineered NK cell engagers that combine tumour targeting with NK activation using cytokines and adoptive NK cell transfer. The immune regulatory and tumour defending potentials of NK cells make them ideal candidates to rewrite the immune strategies against cancer. The advances in NK-cell specific therapeutic frameworks in combination with T-cell–based strategies are very promising, empowering the body’s built-in assassins to programmed soldiers of next generation cancer therapy.

Keywords: Anti-tumour therapy, immune defence, Natural Killer cells, NK cell adoptive transfer, NK Cell engagers, PD-1 therapy.