Machine learning–guided multimodal profiling defines perturbed immune states at the time of cancer diagnosis

Altered immune states at the time of cancer diagnosis remain insufficiently characterized. Although circulating immune biomarkers offer a promising, non-invasive way of analysing systemic tumour–host interactions, their potential remains poorly defined. Here, we present an integrated multi-omics analysis of peripheral blood mononuclear cells from treatment-naïve cancer patients, minimizing confounding by therapy-induced immune changes, combining immune phenotyping (flow cytometry, FC), multiplex cytokine profiling, and single-cell RNA sequencing (scRNA-seq). Compared with healthy donors, patients exhibited widespread immune dysregulation, including expansion of FOXP3+ regulatory T cells, depletion of CD16+CD11b+ monocytes and CD56^dim^ Natural killer (NK) cells, and elevated plasma IL-6 and IL-4 levels. scRNA-seq identified cancer-associated immune signatures, notably consistent upregulation of THBS1 and CH25H, indicative of systemic imprinting by tumour-derived cues. We further developed machine learning-guided models integrating single-cell multi-omics data (sc-FC and scRNA-seq) to characterize cancer-associated immune patterning and cancer type–related signal structure, while providing biologically interpretable feature attribution across modalities. The models achieved robust classification performance within the cohort and revealed modality-spanning features linked to immune state alterations. Together, these findings establish a framework for immune-based, multi-omics profiling of peripheral blood and provide a resource for discovering circulating cancer-associated immune signatures. This supports future development of immune-based diagnostics and disease monitoring approaches.