LncRNA 606938-TFAM axis drives oxidative stress and activates cGAS-STING pathway-mediated antitumor immunity to restrain colorectal cancer progression.

Colorectal cancer (CRC) remains the third most common malignancy and a leading cause of cancer-related mortality worldwide. Despite immunotherapy advances, most CRCs respond poorly to immune checkpoint inhibitors due to their immunologically "cold" phenotype characterized by low immunogenicity and a suppressive tumor microenvironment. Oxidative stress has emerged as a critical determinant of antitumor immunity, with excessive reactive oxygen species (ROS) triggering immunogenic cell death, releasing tumor-associated antigens and damage-associated molecular patterns. However, endogenous mechanisms linking ROS regulation to innate immune activation remain incompletely understood. Here, we identify a previously unreported mitochondria-associated long non-coding RNA, lncRNA 606938, whose expression is inversely correlated with CRC progression. Mechanistically, lncRNA 606938 is exported from the nucleus via the HuR-IGF2BP2 complex and translocated to mitochondria through the mitochondrial targeting sequence and HMG2 domains of mitochondrial transcription factor A (TFAM). Within mitochondria, lncRNA 606938 enhances oxidative phosphorylation (OXPHOS) by upregulating mitochondrial DNA-encoded OXPHOS subunits, leading to excessive ROS production. In addition, lncRNA 606938 facilitates the recognition of N6-methyladenosine (m6A) sites on TFAM mRNA by IGF2BP2, thereby enhancing its stability and expression, further reinforcing mitochondrial oxidative stress. The elevated ROS induces mitochondrial damage and cytosolic release of mitochondrial DNA, which activates the cGAS-STING pathway and stimulates innate immune responses, ultimately suppressing tumor growth. Collectively, our findings highlight lncRNA 606938 as a novel upstream regulator of mitochondrial metabolism and innate immune activation, providing new insights into lncRNA-mediated reprogramming of the tumor immune microenvironment and uncovering a potential therapeutic strategy to sensitize CRC to immunotherapy.