Reengineering immunotherapeutic responses: ferroptosis-primed radiotherapy converts cold-colorectal tumors into immunotherapy checkpoint inhibitor-sensitive hot lesions

While immune checkpoint inhibitors (ICIs) have revolutionized oncology, microsatellite stable (MSS) colorectal cancer (CRC) remains immunologically “cold” and resistant. Ferroptosis, an iron-dependent form of cell death triggered by radiotherapy via reactive oxygen species (ROS) and acyl-CoA synthetase long-chain family member 4 (ACSL4), represents a critical vulnerability. Radiotherapy-induced ferroptosis promotes CD8 + T-cell recruitment; these T cells secrete interferon-γ (IFN-γ) to further repress solute carrier family 7 member 11 (SLC7A11), forming a reciprocal positive feedback loop that amplifies tumor killing. Crucially, we propose a paradigm shift by introducing an inherent “immunosuppressive brake” within this process. Recent evidence has revealed that ferroptotic cancer cells selectively release extracellular glutathione peroxidase 4 (eGPX4). As a novel damage-associated molecular pattern (DAMP), eGPX4 binds to the zona pellucida glycoprotein 3 (ZP3) receptor on dendritic cells (DCs), activating the cyclic adenosine monophosphate–protein kinase A (cAMP‒PKA) signaling cascade to inhibit 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2)-mediated glycolysis. This metabolic hijacking impairs DC maturation and subsequent T-cell priming, limiting the systemic efficacy of ferroptosis-inducing therapies. Therefore, we argue that successfully converting “cold” MSS CRC into a “hot” phenotype requires a dual strategy: maximizing ferroptosis induction while simultaneously neutralizing the eGPX4-ZP3 axis. This integrated approach provides a novel translational framework to overcome immunotherapy resistance, offering fresh hope for the majority of CRC patients.