Immune network remodeling driven by ferroptosis: Bidirectional interaction mechanisms among multiple immune cells in...

The efficacy of immunotherapy for lung cancer is largely constrained by the highly complex and dynamically evolving tumor immune microenvironment (TIME). Previous studies have mainly focused on single immune checkpoints or individual immune cell types, thus hindering the comprehensive elucidation of variations in immune responses and the emergence of resistance. Ferroptosis, a form of programmed cell death characterized by iron‑dependent lipid peroxidation imbalance, has emerged as a pivotal hub linking tumor metabolism, cellular fate and immune regulation due to high dependence on metabolic states and its capacity to release multiple immunomodulatory signals. The unique environment of lung tissue, characterized by high oxygen levels, active lipid metabolism and easily disrupted iron homeostasis, provides a distinct biological foundation for the initiation and amplification of ferroptosis within the lung cancer TIME. Increasing evidence indicates that ferroptosis affects not only tumor cell survival, but also immune regulation. Through lipid peroxidation products, iron‑related metabolites and damage‑associated molecular patterns, it forms bidirectional regulatory networks with multiple immune cell subsets, including CD8⁺ T‑cells, dendritic cells, macrophages, natural killer cells and neutrophils, thereby shaping the functional state of the immune microenvironment. Distinct from previous reviews that broadly discuss ferroptosis in cancer immunity or the tumor microenvironment, the present review specifically focuses on the lung cancer‑specific immune microenvironment and integrates ferroptosis‑mediated bidirectional interactions across multiple immune cell subsets. The present review emphasizes that ferroptosis should not be viewed merely as a tumoricidal form of cell death, but as a context‑dependent immunometabolic hub that drives immune network remodeling in lung cancer. By this conceptual perspective, the present review aimed to provide a novel framework for understanding heterogeneous immunotherapy responses and for designing rational ferroptosis‑based combination strategies.