Combination cancer therapy integrating T-cell immune checkpoint blockers and natural killer cell activation

T-cell immune checkpoint blockers (ICBs) and natural killer (NK) cell activation have emerged as promising strategies for cancer therapy in recent years. In this approach, ICBs target inhibitory receptors on cytotoxic immune cells, such as programmed death Protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1), to enhance immune cell cytotoxicity against cancer cells in a CD8+ T cell-dependent manner. Meanwhile, NK cells play a critical role in immunosurveillance through their direct cytotoxic effects, which do not require prior activation. NK cell activation is mediated by receptors such as NK Group 2 member D (NKG2D), which regulates NK cell function and cytotoxicity through the upregulation of cytokine production. Individually, these treatments target only a limited subset of cancer patients and often face great resistance rates after treatment. However, combining ICBs with NK cell activation may produce a synergistic therapeutic effect, potentially improving treatment outcomes. This perspective article discusses the mechanisms of action of T cell-related PD-1/PDL1 pathways and NK cell activation through NKG2D, examining current studies that provide a rationale for combined NK/T cell combination therapy. The potential of this dual-combination approach to enhance anti-tumor immunity is highlighted. Future perspectives suggest the potential development of chimeric antibodies targeting both T cells and NK cells as a novel therapeutic strategy for cancer treatment.