Overexpression of complement genes in the tumor microenvironment, including Factor H (FH), is a strong predictor of poor prognosis in multiple cancers. Its canonical functions in the bloodborne complement cascade, though, cannot explain this prognostic impact. Here, we demonstrate that FH operates within the intracellular space in fibroblasts and tumor cells. By transcriptomics approach in patient tumors, cellular and biochemical assays we revealed that the prognostic impact of FH overexpression is mediated mainly by its cell-intrinsic functions in tumor-promoting fibroblasts and malignant cells. Intranuclear FH interacts with the cell cycle-transcription factor E2F3. FH also promotes proliferation by lowering the nuclear p53 pool. Moreover, in ccRCC cancer cells, FH also regulates cytoskeleton organization and cell morphology, potentially, via interaction with the actin capping CapZ complex. Therefore, complement FH acts as a multitasking effector, regulating cell cycle and actin polymerization, challenging the paradigm of extracellular space-restricted functioning, considered for many complement proteins.
Artero et al. (2026) studied this question.