Triple-negative breast cancer (TNBC) is highly heterogeneous in prognosis. The current TNM staging system shows its limitation in accurate risk evaluation. Immune response and immune cell abundances in the tumor immune microenvironment (TIME) are critical for cancer progression, clinical outcome and therapeutic response in TNBC. However, there is a lack of an effective risk model based on the overall transcriptional alterations relevant to different immune responses. In this study, multiple bioinformatics and statistical approaches were used to develop an immune-related risk (IRR) signature based on the differentially expressed genes between the immune-active and immune-inactive samples. The IRR model showed great performance in risk stratification, immune landscape evaluation and immunotherapy response prediction. Compared with the low-IRR group, the high-IRR group exhibited a poorer prognosis, less cytotoxic cell infiltration, higher M2/M1 ratio and upregulated glycolytic activity. Moreover, the high-IRR group showed more resistance to immunotherapy than the low-IRR group. Our study reveals that the IRR model may be a promising tool to help clinicians assess risk and optimize treatment for TNBC patients.AJCR Copyright © 2022.