Activation of <scp>cGAS</scp> ‐ <scp>STING</scp> Pathway by <scp>DAI</scp> ‐Triggered Ferroptosis in <scp>CRC</scp> Cells Reprograms <scp>TAMs</scp> Balance to Promote Anti‐Tumor Immunity

DNA-dependent activator of interferon-regulatory factors (DAI) has recently been identified to trigger ferroptosis in endothelial cells. However, it remains unclear whether it can also elicit ferroptosis in tumor cells and further remodel the tumor immune microenvironment (TIME). In this study, we found that activation of DAI could also trigger mouse colorectal cancer (CRC) cells ferroptosis. Further experiments showed that DAI-driven ferroptosis induced mitochondria oxidative stress and dysfunction, leading to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which subsequently activated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and thereby reprogrammed the TIME by promoting tumor-associated macrophages (TAMs) M1 polarization while preventing TAMs from polarizing towards M2 type, exerting an effective anti-tumor effect, which significantly reduced tumor size and weight. In summary, our findings confirmed DAI-triggered ferroptosis-induced mtDNA-mediated cGAS-STING anti-tumor immunity pathway in mouse CRC cells, providing novel insights into the development of more effective tumor immunotherapeutic strategies that are based on DAI-mediated programmed cell death (PCD).