Circulating Proteomic Signatures for Multicancer Early Detection: Cross-Platform Evidence for a Matrix-Immune-Secretory Biomarker Axis.

Blood-based proteomics may complement existing MCED approaches by capturing tumor-secreted proteins and systemic host responses. We reviewed prospective and multicancer studies published from 2020 to 2025 that used Olink, SomaScan, or mass spectrometry and compared evidence from case-control and prospective designs. Candidate proteins were classified as established or novel and evaluated using pathway and cancer-hallmark enrichment analyses, GEPIA3.0 Cox analyses, TCGA Kaplan-Meier survival curves, and TPCPA/RPPA protein abundance data. Across platforms, established markers, including CEACAM5, WFDC2/HE4, and GDF15 were complemented by novel candidates converging on a matrix-immune-secretory axis. This axis included MMP12 and ADAM8, CD74 and CXCL13, TGFB1, and CDCP1. Secretory and matrix-associated candidates were linked to poorer survival in several epithelial cancers, whereas immune-associated proteins showed context-dependent effects. Tumor-type-specific protein elevation supported their detectability, and interaction analysis organized the candidates into biologically coherent modules. These findings support an MCED framework combining higher-risk secretory and matrix markers with immune-context indicators to improve sensitivity and biological interpretation. Prospective validation and down-selection into scalable targeted assays are required before population-level application.