Circulating C1QC in cancer: analytical platforms, evidence gaps, and prospects for clinical chemistry translation

Traditional serum tumor markers, such as carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), cancer antigen 125 (CA 125), α-fetoprotein (AFP), and prostate-specific antigen (PSA), exhibit limited diagnostic sensitivity and specificity during the early stages of disease and in malignancies with overlapping clinical features. This limitation has led to the investigation of complement pathway proteins as potential clinical chemistry analytes. Measurements of circulating complement C1q C chain (C1QC) are frequently derived from total C1q or C1q-binding activity assays, rather than those specific to C1QC. These measurements are linked to the activation of the classical complement pathway, M2-like polarization of tumor-associated macrophages, and immunosuppressive metabolic reprogramming. However, many of the available data are based on transcriptomic analysis of tissues, single-cell analysis, bioinformatic datasets, or small retrospective cohorts without directly measuring the C1QC protein in the circulation. This narrative review critically evaluates C1QC within the clinical chemistry framework, covering its gene structure, proteoform heterogeneity, and post-translational modifications. This study also evaluated the analytical performance metrics of immunoassays, targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS), aptamer-based electrochemical biosensors, and surface plasmon resonance platforms. It critically appraises the reported diagnostic and prognostic associations, including the proposed incremental contributions of multimarker panels. Additionally, external quality assessment, prospective multicenter validation, assay harmonization, and consideration of interference from inflammatory, infectious, or immune-mediated conditions are required for this approach. Compliance with the In Vitro Diagnostic Medical Devices Regulation (IVDR) and United States Food and Drug Administration (FDA) regulatory pathways is also necessary.