Neoadjuvant chemoimmunotherapy (NACi) is a new standard treatment for early-stage high-risk triple-negative breast cancer (TNBC). Desmoplastic reaction (DR) is an important characteristic in the tumor-associated stroma of TNBC. Based on the presence or absence of myxoid stroma and keloid-like collagen bundles within the tumor-associated stroma, DR was classified into immature, intermediate, or mature type. The relationship between DR and NACi efficacy remains unclear. We retrospectively analyzed 209 TNBC patients who received NACi from three medical centers, and 75, 78, and 56 cases were categorized as mature, intermediate, and immature types of DR, respectively. The pathological complete response (pCR) rate was the highest in the mature group (77.3%), followed by the intermediate (30.8%) and immature (17.9%) groups. Multivariate logistic regression analysis indicated that, in addition to histological type, Ki-67, T stage, N stage, and stromal tumor-infiltrating lymphocytes (sTILs), DR was also an independent predictor of pCR. Cases with intermediate and immature stroma exhibited fewer sTILs, an immunosuppressive tumor microenvironment, and upregulation of genes related to extracellular matrix and epithelial-mesenchymal transition. These findings demonstrate the predictive value of DR for NACi efficacy in TNBC and highlight its potential as a histopathological biomarker. The association between DR and molecular hallmarks provides important insights into the biological basis of DR in TNBC.Copyright © 2025. Published by Elsevier Inc.