Abstract
Ovarian cancer comprises a highly complex ecosystem of malignant cells and their surrounding tumor microenvironment (TME), where intricate interactions shape therapeutic responses. Most current predictive models fail to capture the full extent of these interactions. Here, we performed a comprehensive multi-omic analysis of pre-treatment ovarian tumor tissues, integrating clinical, genomic, transcriptomic, and immune features to correlate with pathological therapy response. Our results show that integrating genetic and immune parameters—particularly the interplay between NK cells and TP53 status in high grade serous ovarian cancer (HGSOC), and diverse genetic alterations in non-HGSOC—markedly improves therapy response prediction. We demonstrate that tumor TP53 status governs the persistence of early NK cells in HGSOC, and this persistent NK phenotype is associated with favorable clinical outcomes. Machine learning models harnessing these multi-omic features significantly outperform those based on any single information type alone. These findings highlight the central role of the baseline tumor ecosystem and support a precision oncology framework leveraging integrated multi-omic profiling and advanced analytics to improve prediction and guide treatment strategies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-025-03554-w.