Ferroptosis in Tumor Progression: Metabolic Vulnerabilities, Signaling Crosstalk, and Therapeutic Opportunities

Ferroptosis has emerged as a pivotal frontier in cancer research, where distinct vulnerabilities in iron and lipid metabolism not only influence tumor progression but also reshape the landscape of therapeutic responses. Recent evidence highlights that dysregulated ferroptosis pathways in tumors modulate the microenvironment, enable metastatic competence, foster resistance to conventional and targeted therapies, and simultaneously create new therapeutic windows. Despite remarkable progress in mapping the core machinery of ferroptosis—such as GPX4, FSP1, and ACSL4—and uncovering context-dependent regulators, fundamental questions persist regarding the complex metabolic interplay that underpins ferroptosis sensitivity in tumor progression, chemoresistance, and immune modulation.Current challenges in the field arise from incomplete understanding of how metabolic adaptation enables tumor cells to evade ferroptosis during disease advancement and therapeutic stress, as well as the underutilized potential of ferroptosis induction in clinically refractory settings. Studies have shown that mesenchymal and drug-persistent cancer cells exhibit heightened dependency on ferroptosis defense mechanisms, while immunosuppressive tumor microenvironments shape ferroptosis vulnerability through lipid and iron metabolic crosstalk between malignant and immune compartments. As ferroptosis regulation remains a moving target across genetic contexts and treatment histories, clarifying these mechanisms and their clinical relevance is crucial for the next generation of ferroptosis-based therapeutic strategies.This Research Topic aims to illuminate the key ferroptosis determinants that define tumor progression, chemotherapeutic resistance, and immune evasion within cancer. Specifically, it seeks to identify actionable metabolic nodes conferring ferroptosis resistance, explore combinatorial strategies that potentiate ferroptosis in refractory cancer subsets, and leverage advanced model systems for the validation of ferroptosis-related biomarkers and therapeutic paradigms. By fostering multidisciplinary perspectives across cancer biology, pharmacology, immunology, and chemical biology, the goal is to bridge the gap between mechanistic discoveries in ferroptosis and clinically actionable strategies, ultimately advancing new paradigms for precision oncology.The scope of this Research Topic spans three interconnected thematic axes:Axis 1 – Ferroptosis in tumor progression: Submissions should focus on mechanistic, translational, or model-based investigations linking ferroptosis regulators to cancer hallmarks such as proliferation, metastasis, stemness, and metabolic reprogramming. Studies elucidating crosstalk between ferroptosis and oncogenic signaling pathways (e.g., p53, KRAS, HIF-1α, NRF2) or identifying context-dependent ferroptosis vulnerabilities during tumor evolution are particularly welcome.Axis 2 – Ferroptosis in cancer chemotherapy: Submissions should address how conventional chemotherapeutic agents intersect with ferroptosis pathways, how acquired chemoresistance alters ferroptosis sensitivity, and how ferroptosis inducers can be deployed to resensitize refractory tumors. Contributions identifying predictive biomarkers for ferroptosis-based chemosensitization or leveraging organoid platforms for drug combination screening are strongly encouraged.Axis 3 – Ferroptosis in cancer immunology: Submissions should explore the bidirectional regulation between ferroptosis and antitumor immunity, including how immune cells (e.g., CD8+ T cells, macrophages) influence and are influenced by ferroptotic death in the tumor microenvironment. Studies investigating ferroptosis as a determinant of immune checkpoint blockade efficacy, or proposing ferroptosis–immunotherapy combination regimens, are of high priority.We welcome contributions addressing, but not limited to, the following themes:• Metabolic and signaling drivers of ferroptosis vulnerability or resistance during tumor progression• Mechanisms by which chemotherapeutic agents engage or evade ferroptosis; ferroptosis-based strategies to overcome acquired drug resistance• Immune–ferroptosis metabolic crosstalk and its impact on checkpoint activity and antitumor immunity• Ferroptosis-based interventions and the identification of synthetic lethal interactions in refractory cancer subsets• Ferroptosis drug screening and biomarker discovery• Innovative cross-disciplinary approaches integrating multi-omics, lipidomics, CRISPR screens, and computational modeling to dissect ferroptosis regulation Topic editors: Huizhen Sun, Xue Wang, Cheng Zhan, Anwar Azad Palakkan Source: https://www.frontiersin.org/research-topics/81427/ferroptosis-in-tumor-progression-metabolic-vulnerabilities-signaling-crosstalk-and-therapeutic-opportunities