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

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.