ArticleJournal of translational medicine2025
Focal hotspot and diffuse immune subtypes of tumor-infiltrating lymphocytes: AI-powered spatial clustering classification and its clinical relevance to HER2 expression in triple-negative breast cancer.
Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Beyond pCR Prediction: Subtype-Specific Artificial Intelligence for Treatment Tailoring in Breast Cancer Neoadjuvant Therapy.Cancers · 2026Review
- From counting to clustering: AI-defined "diffuse" vs. "focal" spatial patterns as the new precision biomarker for triple-negative breast cancer.Frontiers in immunology · 2026Article
- An integrated automated deep learning framework for annotating tumor-infiltrating lymphocytes in lung adenocarcinoma pathology.Frontiers in bioinformatics · 2026Article
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Abstract
purposeThis study aimed to define spatial immune subtypes of tumor-infiltrating lymphocytes (TILs) using artificial intelligence (AI)-powered analysis and investigate their association with distinct human epidermal growth factor receptor-2 (HER2) expression levels, response to neoadjuvant chemotherapy (NAC), and patient survival outcomes in triple-negative breast cancer (TNBC).
methodsWe conducted a multicenter study involving TNBC patients receiving NAC, stratified into HER2-0, HER2-ultralow, and HER2-low subgroups. An AI-based cell classifier was employed to identify TILs (AI-TILs) and extract spatial coordinates from pathology images. Using unsupervised learning of spatial clustering analysis to identify immune subtypes. The performance of the AI model was benchmarked against four experienced pathologists. Associations among TILs spatial subtypes, HER2 status, NAC response including pathologic complete response (pCR) and residual cancer burden (RCB), and survival outcomes were systematically evaluated.
resultsAI-TILs demonstrated strong agreement with both senior pathologists, and unsupervised clustering revealed two spatial subtypes: the focal hotspot subtype and the diffuse immune subtype, the latter exhibited broader TIL hotspot areas, lower peak densities, higher pCR rates, and significantly prolonged disease-free survival (DFS). RCB-III status was inversely associated with the diffuse immune subtype, suggesting a link between diffuse immune subtype and good NAC response. Postmenopausal status was independently linked to the focal hotspot pattern. Although HER2 expression was associated with TILs spatial subtypes, it was not an independent influencing factor. In the HER2-low subgroup, the diffuse subtype was significantly associated with better pCR and lower RCB scores, whereas no such relationship was observed in HER2-0 or HER2-ultralow groups. Alluvial and standardized residual analysis further validated that focal hotspot/HER2-low tumors were enriched in RCB-III (residual = 3.26), while diffuse/HER2-low tumors were enriched in RCB-0 (residual = 1.30), suggesting divergent trajectories of immune architecture and chemoresponsiveness.
conclusionThis study distinguished focal hotspot and diffuse immune subtypes of TILs with distinct clinical implications in TNBC. The diffuse immune subtype correlated with enhanced NAC response and favorable prognosis, particularly in HER2-low TNBC. These findings highlighted the spatial immune architecture as a promising biomarker to refine treatment stratification and deepen our understanding of immune heterogeneity in HER2-low TNBC.
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