Complement factor H in cancer biology: intracellular functions, tumor-host interactions, and systemic context

Complement factor H (FH), encoded by CFH, is a principal soluble regulator of the alternative complement pathway, but its roles in cancer extend beyond extracellular complement control. Intracellular FH has been linked to p53/NF-κB signaling, cell-cycle regulation, and cytoskeletal organization. Recent studies distinguish a nuclear FH-E2F3 interaction associated with p53 and cell-cycle control from a cytosolic FH-CapZ-associated mechanism involved in actin organization. Although FH has been detected in lysosome-positive compartments, current evidence does not establish lysosomes as the functional site of these intracellular effects. At the tumor-host interface, extracellular FH protects tumor-cell and extracellular-vesicle surfaces from complement-mediated injury and phagocytic clearance. Locally produced FH and FHL-1 have also been associated with distinct myeloid-cell and regulatory T-cell programs, including direct FH-ICOS engagement. Structurally altered tumor-associated FH can become a target of endogenous anti-FH antibodies and of the therapeutic antibody GT103, linking local complement regulation with humoral recognition and therapeutic intervention. Across tissues and circulation, FH exists in intracellular, soluble, surface-associated, and extracellular-vesicle-associated pools shaped by hepatic production, local synthesis, surface recruitment, distribution, and clearance. These pools are not interchangeable: their functions and clinical associations depend on both source and compartment. We therefore propose a source- and compartment-resolved framework that separates systemic FH availability from local intracellular and extracellular functions, while treating cross-compartment relationships as testable rather than established causal sequences. Tissue and circulating FH measurements are being explored as context-dependent biomarkers, and GT103 has progressed through phase Ib and completed phase II evaluation in refractory non-small cell lung cancer. Further progress will require tissue-specific experimental models, paired tissue and circulating measurements, clearer mapping of intracellular interaction sites, and biomarker analyses that account separately for hepatic production, inflammatory state, renal handling or protein loss, and altered distribution or clearance.