Insights and perspectives into the discovery of complement-related biomarkers in cancer

The complement system, a central component of innate immunity, is implicated in tumor biology, influencing processes such as tumor progression, immune evasion, and response to therapy. Numerous studies have identified alterations in complement effectors, activation products, regulatory proteins, and receptors in patients with cancer. These findings underscore the potential of complement-derived biomarkers for enhancing cancer diagnosis, prognosis, or treatment guidance across various oncology settings. However, despite substantial progress in discovery and early validation, no complement-related biomarker has yet been integrated into routine oncology practice. Key challenges in the field include the biological complexity of the complement system, variability in testing methods, and the lack of standardized protocols for sample collection, processing, and analysis. Addressing these issues is essential to ensure reliable and reproducible measurements. Moreover, the clinical utility of these biomarkers depends on their validation in real-world settings, as well as their integration with other molecular markers, advanced imaging, radiomics, and artificial intelligence tools. Advancing the development of harmonized assays and reference materials will be critical for the translation of complement biomarkers into clinical use in cancer. This review summarizes current knowledge on complement-related biomarkers in oncology, highlights technical and conceptual challenges, and discusses future directions to fully harness the potential of the complement system in cancer care.