Spatial proteomics guided by H&E-based AI reveals recurrence-risk niches in triple-negative breast cancer

Computer Science > Artificial Intelligence [Submitted on 4 Aug 2026] Spatial proteomics guided by H&E-based AI reveals recurrence-risk niches in triple-negative breast cancer Yesung Cho, Ji Hwan Park, Chanil Kim, Hyewon Kim, Honglan Li, Yumin Lee, Geongyu Lee, Sujeong Hong, Seong Min Park, Yoonyoung Lee, Hee Sool Rho, Sumin Lee, Amos Chungwon Lee, Changhwan Lee, Hwanyoung Shim, Hyunwook Kim, Hyeji Shin, Sanha Park, Jihoon Yu, Yoon Hee Shin, Sooheon Kim, Hyunjin Park, Seung Min Park, Sangwan Kim, Yujung Kim, Sung-Im Do, Eun-Young Kim, Dongmyung Shin, Jongbae Park, In-Gu Do Deep learning models can predict cancer recurrence from H&E stained slides, but the localized molecular states underlying these predictions remain largely obscured. Here, we developed an outcome informed spatial pathology framework in TNBC that integrates AI generated recurrence risk heatmaps with mass spectrometry based spatial proteomics. In a cohort of 156 patients, distribution based aggregation of high scoring patches achieved an AUC of 0.77 and a C-index of 0.77 in an independent test cohort. Bulk proteomics associated high image derived risk with cell cycle and genome maintenance programs and low risk with immune activation. High and low risk patches coexisted within the same tumor compartment and displayed distinct nuclear and architectural features, revealing intratumoral heterogeneity beyond tissue compartment identity. We then used the heatmaps as coordinate level guides to physically isolate and profile 46 AI defined tumor regions from two recurrence patients. Spatial proteomic profiling revealed a concordant molecular contrast across both patients: mitotic programs were enriched in high risk regions and immune and antigen presentation programs in low risk regions. A 13 protein composite derived from these spatial contrasts showed a trend toward poorer recurrence-free survival with increasing scores in an expanded cohort, while the corresponding transcript based composite stratified recurrence free survival in the independent METABRIC TNBC cohort. Integrating the protein composite with the H&E derived risk score improved the out of bag C-index from 0.679 to 0.739 and enhanced time dependent discrimination at 3 and 5 years. Together, these findings define a new role for outcome trained AI models as spatially explicit experimental guides that connect prognostic morphology with localized molecular states and advance biologically grounded, multiscale biomarker discovery in TNBC. Comments: Triple-negative breast cancer (TNBC), Recurrence, Digital pathology, Artificial intelligence, Spatial proteomics, Tumor microenvironment Subjects: Artificial Intelligence (cs.AI); Quantitative Methods (q-bio.QM) Cite as: arXiv:2608.03145 [cs.AI]   (or arXiv:2608.03145v1 [cs.AI] for this version)   https://doi.org/10.48550/arXiv.2608.03145 Focus to learn more Submission history From: Geongyu Lee [view email] [v1] Tue, 4 Aug 2026 05:19:35 UTC (1,330 KB) Access Paper: view license Current browse context: cs.AI < prev   |   next > new | recent | 2026-08 Change to browse by: cs q-bio q-bio.QM References & Citations NASA ADS Google Scholar Semantic Scholar Export BibTeX Citation Bookmark Bibliographic Tools Bibliographic and Citation Tools Bibliographic Explorer Toggle Bibliographic Explorer (What is the Explorer?) Connected Papers Toggle Connected Papers (What is Connected Papers?) Litmaps Toggle Litmaps (What is Litmaps?) scite.ai Toggle scite Smart Citations (What are Smart Citations?) Code, Data, Media Demos Related Papers About arXivLabs Which authors of this paper are endorsers? | Disable MathJax (What is MathJax?)