Academic Journal
Complement factor H in cancer biology: intracellular functions, tumor-host interactions, and systemic context.
| Title: | Complement factor H in cancer biology: intracellular functions, tumor-host interactions, and systemic context. |
|---|---|
| Authors: | Wang X; Department of Oncology, Zibo Central Hospital, Zibo, China., Mu M; Department of Oncology, Zibo Central Hospital, Zibo, China., Li H; Department of Oncology, Zibo Central Hospital, Zibo, China. |
| Source: | Frontiers in immunology [Front Immunol] 2026 Jul 29; Vol. 17, pp. 1877625. Date of Electronic Publication: 2026 Jul 29 (Print Publication: 2026). |
| Publication Type: | Journal Article; Review |
| Language: | English |
| Journal Info: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation] |
| MeSH Terms: | Neoplasms*/immunology , Neoplasms*/metabolism , Neoplasms*/pathology , Complement Factor H*/immunology , Complement Factor H*/metabolism, Humans ; Animals ; Signal Transduction |
| Abstract: | 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. (Copyright © 2026 Wang, Mu and Li.) |
| Competing Interests: | The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
| References: | Nat Rev Nephrol. 2018 Jan;14(1):26-47. (PMID: 29199277) World J Urol. 2012 Dec;30(6):869-73. (PMID: 22932760) Exp Ther Med. 2019 May;17(5):4073-4079. (PMID: 31007744) Mol Cancer Ther. 2023 Jun 1;22(6):778-789. (PMID: 36995981) Front Oncol. 2022 Oct 20;12:812663. (PMID: 36338737) J Invest Dermatol. 2014 Feb;134(2):498-506. (PMID: 23938460) Oncoimmunology. 2024 Mar 13;13(1):2328433. (PMID: 38487624) Biochemistry. 2013 Jun 11;52(23):3949-62. (PMID: 23701234) Oncogene. 2012 Mar 1;31(9):1130-42. (PMID: 21804603) Semin Immunol. 2025 Jun;78:101950. (PMID: 40179675) Anal Chem. 2023 Aug 1;95(30):11440-11448. (PMID: 37478154) J Oncol. 2022 Sep 30;2022:1752827. (PMID: 36213819) Clin Cancer Res. 2021 Dec 1;27(23):6514-6528. (PMID: 34479957) Cancer. 2025 Nov 1;131(21):e70141. (PMID: 41129008) Science. 2005 Apr 15;308(5720):385-9. (PMID: 15761122) J Cell Biochem. 2020 Apr;121(4):2970-2980. (PMID: 31709629) Cancers (Basel). 2019 Apr 03;11(4):. (PMID: 30987235) Cancers (Basel). 2025 Jun 26;17(13):. (PMID: 40647461) PLoS One. 2021 Jun 16;16(6):e0252577. (PMID: 34133431) Nat Rev Immunol. 2018 Jan;18(1):5-18. (PMID: 28920587) Immunity. 2023 Aug 8;56(8):1809-1824.e10. (PMID: 37499656) Int Immunopharmacol. 2025 May 8;154:114544. (PMID: 40157080) Nat Commun. 2025 Jan 2;16(1):93. (PMID: 39747856) Open Life Sci. 2022 Mar 23;17(1):248-260. (PMID: 35415236) Biosens Bioelectron. 2018 Oct 15;117:620-627. (PMID: 30005382) Oncogene. 2025 May;44(17):1197-1203. (PMID: 40210758) Commun Biol. 2026 Mar 05;9(1):. (PMID: 41781748) Cancer Epidemiol Biomarkers Prev. 2010 Oct;19(10):2665-72. (PMID: 20802023) Clin Cancer Res. 2010 Jun 15;16(12):3226-31. (PMID: 20515868) Bioengineered. 2022 May;13(5):12193-12210. (PMID: 35549979) Nat Immunol. 2008 Nov;9(11):1225-35. (PMID: 18820683) Ecotoxicol Environ Saf. 2025 Jun 15;298:118335. (PMID: 40373713) Cell Mol Life Sci. 2017 May;74(9):1605-1624. (PMID: 27942748) Front Immunol. 2024 Feb 12;15:1135490. (PMID: 38410512) Cancer Immunol Immunother. 2025 Feb 26;74(4):126. (PMID: 40009215) Nat Rev Immunol. 2019 Aug;19(8):503-516. (PMID: 31048789) J Korean Med Sci. 2011 Nov;26(11):1428-38. (PMID: 22065898) Med Sci Monit. 2018 Aug 16;24:5704-5712. (PMID: 30111766) Oral Oncol. 2024 Dec;159:107078. (PMID: 39437531) Immunity. 2013 Dec 12;39(6):1143-57. (PMID: 24315997) Cancer Immunol Res. 2025 Jan 9;13(1):122-138. (PMID: 39378431) Aging (Albany NY). 2022 Jul 18;14(14):5783-5799. (PMID: 35852862) J Immunol. 2009 May 1;182(9):5412-8. (PMID: 19380788) Trends Immunol. 2008 Aug;29(8):380-7. (PMID: 18602340) J Proteome Res. 2013 Jul 5;12(7):3342-52. (PMID: 23731285) Kidney Int. 2021 Oct;100(4):824-836. (PMID: 34139209) Mol Genet Genomic Med. 2024 Jan;12(1):e2289. (PMID: 37803932) Int J Mol Sci. 2021 Aug 13;22(16):. (PMID: 34445430) Eur J Neurosci. 2022 Mar;55(5):1278-1290. (PMID: 34963193) Front Immunol. 2019 Jul 11;10:1607. (PMID: 31354740) Eur J Immunol. 2016 Jul;46(7):1563-73. (PMID: 27184294) Immunobiology. 2018 Dec;223(12):761-771. (PMID: 30107932) Ann Clin Lab Sci. 2022 Nov;52(6):967-975. (PMID: 36564071) Mol Immunol. 2013 Dec 15;56(3):170-80. (PMID: 23830046) Postgrad Med J. 2022 Dec 1;98(1166):919-924. (PMID: 37063027) Int J Oncol. 2020 May;56(5):1199-1211. (PMID: 32319580) NPJ Precis Oncol. 2025 Mar 3;9(1):58. (PMID: 40032924) Cancer Med. 2024 Jul;13(13):e7394. (PMID: 38970307) Hepatology. 2019 Aug;70(2):725-736. (PMID: 30653682) Nat Immunol. 2010 Sep;11(9):785-97. (PMID: 20720586) J Immunother Cancer. 2026 Mar 11;14(3):. (PMID: 41819546) Cancer Immunol Res. 2021 Aug;9(8):909-925. (PMID: 34039652) Front Genet. 2021 Jun 11;12:670727. (PMID: 34211499) J Immunol. 2024 May 15;212(10):1589-1601. (PMID: 38558134) Cancer Biomark. 2022;34(3):385-392. (PMID: 35068447) Nephrology (Carlton). 2024 Aug;29(8):519-527. (PMID: 38604995) |
| Contributed Indexing: | Keywords: CAPZ; E2F3; GT103; anti-FH autoantibodies; biomarkers; complement Factor H; intracellular FH; systemic context |
| Substance Nomenclature: | 80295-65-4 (Complement Factor H) |
| Entry Date(s): | Date Created: 20260813 Date Completed: 20260813 Latest Revision: 20260814 |
| Update Code: | 20260814 |
| PubMed Central ID: | PMC13463187 |
| DOI: | 10.3389/fimmu.2026.1877625 |
| PMID: | 42592211 |
| Database: | MEDLINE |
| ISSN: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2026.1877625 |