Advances in ferroptosis: Synergistic therapies and fluorescent probes as arrows to target cancer's achilles heel

The robust survival capabilities and adaptability of tumor tissues render them akin to the “Achilles” of the medical field, prompting relentless endeavors to identify and attack their "Achilles' heel". The highly active oxidative-reductive environment within tumor tissues highlights pathways such as glutathione (GSH), iron ions, reactive oxygen species (ROS), and reactive sulfur species (RSS) as potential vulnerabilities, akin to the mythical weakness of Achilles. As biological research delves deeper, one such closely associated “arrow” – Ferroptosis – has emerged, presenting a novel regulatory cell death mechanism. Significantly, integrating Ferroptosis with innovative tumor treatments promises heightened efficacy while minimizing side effects, providing extensive prospects and developmental value in oncology. Within this review we outline the use of Ferroptosis in conjunction with Photothermal Therapy (PTT), Photodynamic Therapy (PDT), Chemodynamic Therapy (CDT), Immunotherapy Therapy (IMT), and multi-therapy approaches for oncological treatments, summarizing the clinical application prospects and challenges, thus offering novel insights into advanced tumor therapies. Nevertheless, the mechanistic intricacies and signaling pathways underlying Ferroptosis, as an “arrow” in tumor therapy, remain poorly understood, possibly due to current research tools', which exhibit limitations associated with the selectivity and sensitivity of imaging Ferroptosis within complex biological environments. To facilitate tracking and the evaluation of this potent “arrow” aimed at the tumor's “Achilles' heel,” this review outlines the use of fluorescent probes targeting iron ions, ROS, RSS, and intracellular microenvironments during Ferroptosis. Emphasis is placed on probe analysis, design strategies and corresponding biological model applications. We also highlight research limitations and provide recommendations, which we hope will empower scholars and researchers to master the use of Ferroptosis as a crucial “arrow” targeting cancers "Achilles' heel". This review aims to promote effort toward removing the “Achilles” of humanity – cancer – and usher in an era of victory against this formidable foe.