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

Abstract

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.