Abstract
Onco-fetal reprogramming of the tumor ecosystem induces fetal-like characteristics, leading to tumor growth and malignant progression. Here, we develop a robust computational pipeline to systematically identify onco-fetal (OF) cells, using single-cell transcriptomic data from corresponding fetal and tumor tissues across multiple cancer types. OF cells are consistently detected across diverse malignancies and exhibit pronounced stem-like properties. Core transcription factors involved in onco-fetal reprogramming are identified, including PTMA, ATF5, TCF4, and FOS, whose coordinated activities may promote tumor progression. Strategically positioned OF cells orchestrate tumor microenvironment crosstalk, specifically impairing B cell function. OF cells are further verified in additional cancers, and we find that high OF cell abundance contributes to enhanced drug resistance and cancer recurrence. Critically, pancancer analyses establish that OF cell markers universally portend adverse prognoses. Overall, our study uncovers a clinically consequential cancer cell subpopulation and highlights its potential as a target for precision oncology.