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.