Ferroptosis as a therapeutic target in cancer: mechanisms, immune interactions, and emerging strategies

Ferroptosis is a novel form of programmed cell death defined by iron-dependent, reactive oxygen species (ROS)-mediated peroxidation of membrane phospholipids containing polyunsaturated fatty acyl chains. Since 2020, research interest in ferroptosis has surged exponentially, outpacing that of other cell death modalities and establishing it as a pivotal regulatory target in oncology. This review offers three key novel contributions compared to prior summaries: first, it systematically integrates the context-dependent roles of ferroptosis either synergistic sensitization or resistance in cancer multi-disciplinary treatment (MDT), including chemotherapy, targeted therapy, radiotherapy, interventional therapy and immunotherapy, with a focus on clinical trial evidence from the past five years; second, it deciphers the dynamic crosstalk between ferroptosis and core components of the tumor immune microenvironment (TIME), while clarifying the regulatory impacts of microenvironmental factors (pH, hypoxia, gut microbiota); third, it comprehensively summarizes breakthrough advances in nanoplatform based ferroptosis regulation, structured around two complementary perspectives: endogenous TME-responsive systems and exogenous stimulus triggered systems. This review aims to bridge basic mechanisms with clinical applicability, providing a framework for translating ferroptosis targeted strategies into optimized MDT regimens.