Microenvironment-Driven modulation of Diiron(I) bis-cyclopentadienyl complexes activity in advanced cancer models

The clinical success of platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin is still limited by severe side effects and the frequent emergence of resistance, highlighting the need for new metal-based anticancer agents. Among potential alternatives, iron is particularly attractive due to its abundance, biocompatibility, and essential biological roles. Despite this potential, complexes based on nonendogenous Fe(I) remain overlooked in cancer therapy. Here, we investigate four diiron(I) bis-cyclopentadienyl complexes bearing aminocarbyne, thiocarbyne, or vinyliminium ligands (FEAMP, FEACYP, FETPY, and FEVCY), previously identified as promising anticancer candidates. Their cytotoxic activity was first evaluated across several cancer cell lines, including breast adenocarcinoma, glioblastoma, and osteosarcoma, together with mechanistic studies focusing on reactive oxygen species (ROS) modulation and the activation of programmed cell-death pathways. Crucially, the study examines how the tumour microenvironment influences drug response. Since conventional 2D cultures often fail to capture the structural and biochemical complexity of tumours, the activity of the iron complexes was further evaluated comparing models of increasing biological relevance: monolayer of cells (MG63 cells), spheroids enriched in Cancer Stem Cells (CSCs Model) and a 3D scaffold-based osteosarcoma model (3D sOS Model) that better reproduces cell-cell and cell-matrix interactions. By integrating multiple experimental systems, this work highlights the critical role of microenvironmental complexity in shaping drug efficacy and provides new insight into the therapeutic potential of low-valent iron complexes as next-generation metal-based anticancer agents.