ABSTRACT Triple‐negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options, and impairment of natural killer (NK) cell cytotoxicity within the tumour microenvironment remains a major challenge. The present study investigated the role of the NogoA/Nogo receptor 1 (NgR1) axis in modulating NK cell–mediated cytotoxicity against TNBC cells. NK‐92 and MDA‐MB‐231 cells were co‐cultured at optimised effector‐to‐target ratios, followed by treatment with the NgR1 antagonist NEP1‐40. Cell viability was assessed by WST‐1 assay, apoptosis was evaluated using AO/DAPI staining, gene expression was analysed by RT‐PCR, and downstream pathways together with immune infiltration were examined in silico. Blockade of NogoA/NgR1 signalling increased NK‐92–mediated cytotoxicity ( p < 0.0001). NEP1‐40 reduced tumour cell viability from approximately 81% to 50% and significantly increased apoptotic cell death ( p < 0.0001). Expression analysis revealed repression of oncogenic and migration‐associated genes, including CDK4, MYC, NF‐κB1, VEGFA, FGF1, N‐cadherin and CD155, consistent with enhanced NK cell–mediated cytotoxicity and reduced tumour immune evasion. Functional annotation identified the PI3K/AKT pathway alongside cell cycle–related processes as candidate downstream mechanisms, while correlation analysis showed that most NogoA‐regulated genes were significantly negatively associated with NK cell infiltration ( p < 0.05), highlighting their role in immune escape. These findings suggest that NogoA regulates both tumour behaviour and immune remodelling in TNBC by enhancing NK cell–mediated cytotoxicity, promoting apoptosis and suppressing immune evasion pathways. Targeting the NgR1/NogoA axis may therefore represent a promising approach to strengthen NK cell–based immunotherapy, offering a novel therapeutic avenue in TNBC.
Korak et al. (Sun,) studied this question.