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Fe-S Protein FDX1 Triggers Tumor-Intrinsic Innate Immunity via Mitochondrial Nucleic Acids Release to Orchestrate
Xing Huang1, Shaoqing Yu1, Wenjie Wei2
1Senior Department of Urology, Chinese PLA General Hospital, Beijing, 100039, China.
Abstract:
Activation of cytosolic nucleic acid-sensing pathways represents a promising strategy to convert immunologically "cold" tumors into inflamed ones. Iron-sulfur (Fe-S) enzymes are critical regulators of innate immunity and nucleic acid sensing, yet their roles in cancer remain poorly defined. Here, ferredoxin-1 (FDX1), a mitochondrial Fe-S protein frequently downregulated in clear cell renal cell carcinoma (ccRCC), is identified as a dual regulator of ferroptosis and antitumor immunity. FDX1 overexpression triggers mitochondrial permeability transition pore opening, leading to cytosolic release of mitochondrial DNA (mtDNA) and double-stranded RNA (mt-dsRNA). This reveals an independent function of FDX1 as a tumor-intrinsic immunity activator linked to mitochondrial stress signaling. These damage-associated molecular patterns (DAMPs) engage cytosolic nucleic acid sensors-specifically cGAS and RIG-I/MDA5-triggering TBK1 phosphorylation and a robust type I interferon response that occurs prior to overt ferroptosis. This innate immune cascade reshapes the tumor microenvironment by enhancing MHC I/II antigen presentation, recruiting CD8+ T cells, and suppressing tumor growth and metastasis in orthotopic syngeneic models. These findings uncover a previously unrecognized antitumor axis through which FDX1 synergizes with mitochondrial nucleic acid release with ferroptosis to promote immunogenic inflammation and T cell infiltration in ccRCC, offering novel therapeutic opportunities targeting mitochondrial-immune crosstalk.
Insights
Ferredoxin-1 (FDX1) activates innate immunity by releasing mitochondrial DNA and RNA, promoting T cell infiltration and suppressing clear cell renal cell carcinoma (ccRCC) growth. This dual regulator of ferroptosis and immunity offers new therapeutic avenues.
Area of Science:
- Immunology
- Oncology
- Mitochondrial Biology
Background:
- Cytosolic nucleic acid sensing pathways can 'warm' cold tumors for immunotherapy.
- Iron-sulfur (Fe-S) enzymes regulate innate immunity and nucleic acid sensing, but their cancer roles are unclear.
- Ferredoxin-1 (FDX1), an Fe-S protein, is often downregulated in clear cell renal cell carcinoma (ccRCC).
Purpose of the Study:
- To investigate the role of Ferredoxin-1 (FDX1) in clear cell renal cell carcinoma (ccRCC).
- To explore FDX1's function as a regulator of ferroptosis and antitumor immunity.
- To understand the mechanism linking mitochondrial stress, nucleic acid release, and immune activation in ccRCC.
Main Methods:
- Investigated FDX1's role in ccRCC using molecular biology techniques.
- Analyzed FDX1-induced mitochondrial changes and cytosolic nucleic acid release.
- Assessed the impact of FDX1 on cytosolic nucleic acid sensors (cGAS, RIG-I/MDA5) and type I interferon response.
- Evaluated the effects on tumor microenvironment, T cell infiltration, and tumor growth in preclinical models.
Main Results:
- FDX1 overexpression triggers mitochondrial permeability transition, releasing mitochondrial DNA (mtDNA) and double-stranded RNA (mt-dsRNA) into the cytosol.
- Released mtDNA and mt-dsRNA activate cGAS and RIG-I/MDA5 sensors, inducing TBK1 phosphorylation and a type I interferon response.
- This innate immune activation precedes ferroptosis, enhances MHC antigen presentation, recruits CD8+ T cells, and suppresses tumor growth and metastasis.
- FDX1 acts as a tumor-intrinsic immunity activator linked to mitochondrial stress signaling.
Conclusions:
- FDX1 is a dual regulator of ferroptosis and antitumor immunity in ccRCC.
- FDX1 promotes immunogenic inflammation and T cell infiltration by linking mitochondrial nucleic acid release with ferroptosis.
- Targeting the mitochondrial-immune crosstalk mediated by FDX1 presents novel therapeutic opportunities for ccRCC.
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