Abstract Circulating tumor cells (CTCs) provide a minimally invasive window into cancer biology and metastatic progression. However, their phenotypic heterogeneity extends beyond classical epithelial marker expression to include subsets with immune features. Using high-resolution single-cell genomic and proteomic profiling of peripheral blood from patients with stage 4 breast cancer, we identified a distinct population of immune-like CTCs (im.CTCs) that co-express epithelial and immune markers, including CD45, CD3, and CD4. These im.CTCs share clonal, tumor-specific genomic alterations with canonical epithelial CTCs, indicating a non-fusion origin and supporting the existence of a previously unrecognized tumor cell plasticity state. We further observed direct physical interactions between circulating white blood cells, predominantly CD4+ T cells, and both im.CTCs and immune marker–positive large extracellular vesicles (im.LEVs) in patient blood samples. Immune membrane markers were enriched at sites of cell–cell contact, consistent with membrane transfer as a mechanism by which tumor-derived circulating analytes acquire immune features. Together, these findings demonstrate that tumor–immune cell interactions in circulation contribute to the emergence of hybrid phenotypes among circulating tumor analytes. This phenomenon has important implications for liquid biopsy interpretation, immune modulation, and the biology of metastatic dissemination. Future work will be required to define the functional consequences of immune marker expression on CTCs and extracellular vesicles and to determine how these interactions influence immune surveillance, metastatic potential, and clinical outcomes. Citation Format: Stephanie N. Shishido, Peter Kuhn, James Hicks, Nikki Higa, Amin Naghdloo, Mohamed Kamal, Dean Tessone, Valerie Hennes, Audrey Limb, Andres Rivera, Rafael Nevarez, Anand Kolatkar, Carol K. Tweed, Adam I. Riker, Young Lee, Lorraine Tafra, Jeremy Perkins, Craig D. Shriver. Immune-Like Circulating Tumor Cells and Large Extracellular Vesicles in Metastatic Breast Cancer abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-C012.
Shishido et al. (Thu,) studied this question.