Fe‐S Protein FDX1 Triggers Tumor‐Intrinsic Innate Immunity via Mitochondrial Nucleic Acids Release to Orchestrate Ferroptosis in CCRCC

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.