AI-enabled Spatial Profiling of Circulating Tumor-Immune Ecosystems Predicts Patient Outcomes Across Cancers

Circulating tumor cells (CTCs) and immune cells form dynamic multicellular ecosystems in blood, but their spatial organization and clinical relevance have not been systematically characterized. We developed the Cell and Cluster Identification Program (CCIP), an artificial intelligence–based framework that analyzes routine multiplex immunofluorescence blood scans to segment cells, identify CTCs and five immune lineages with high accuracy, and quantify multicellular clusters and tumor–immune interactions. Applying CCIP to 2,693 blood scans from 1,399 patients, we profiled over 60 million cells (>7 million multi-cell clusters) and linked imaging-derived features to patient outcomes. Correlated with circulating-tumor DNA mutation burdens, a 14-feature image model predicted overall survival in breast cancer, outperformed clinicopathologic variables and CTC enumeration, and generalized to prostate cancer. Prognostic imaging signatures were also associated with therapy response-related progression-free survival as well as with single-cell RNA sequencing–derived immune suppression states, connecting circulating tumor–immune architecture with systemic immune dysfunction.Competing Interest StatementThe authors have declared no competing interest.The data supporting the findings of this study are available in the Supporting Data Values file. Human scRNA-seq datasets generated in this study are available at GSE294399(19): https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294399. The entire set of scanned immuno-fluorescence images of patient blood and pre-calculated image features and type prediction for individual cells, as well as cell-cluster features can be downloaded through Globus upon requests: https://app.globus.org/file-manager?origin_id=75af3eb6-b480-4f19-882c-ed079225b0ec&origin_path=%2F.National Institutes of Health, https://ror.org/01cwqze88, R01CA245699, R01AI167272, R01CA298232, T32 CA009560Chan Zuckerberg Biohub Chicago, https://ror.org/014nxkk19American Cancer Society, CSCC-Team-23-980420-01-CSCCProstate Cancer Foundation, Challenge Award 2017CHAL2008NIDDK training grant, U2CDK129917, TL1DK132769Lynn Sage Breast Cancer Research FoundationNorthwestern University, Pharmacology start-up grant