The RELA-FTH1 axis in senescent cancer-associated fibroblasts creates a stromal iron sink that drives ferroptosis resistance and therapy failure across solid malignant tumors

BACKGROUND: Therapy resistance remains the foremost barrier to improving outcomes in solid malignancies. While tumor-cell-intrinsic resistance mechanisms have been extensively studied, the contribution of the tumor microenvironment (TME) to treatment failure is poorly understood. Cellular senescence accumulates across diverse solid tumor types and reshapes the stromal landscape, yet which population dominates this senescent compartment and how senescent cancer-associated fibroblasts (senCAFs) drive resistance remain unresolved. In particular, whether senescent fibroblasts can suppress ferroptosis in neighboring tumor cells-and thereby promote drug resistance-through metabolic reprogramming of iron homeostasis has not been mechanistically dissected. METHODS: We integrated six single-cell RNA sequencing datasets (431,513 cells) to map the senescent landscape of the TME. A 24-gene prognostic senescent fibroblast signature was constructed using LASSO/Cox regression and validated in independent TCGA cohorts. Transcription factor prediction and protein-DNA molecular docking identified upstream regulators. Functional studies employed conditioned medium assays, transwell co-culture systems with ferroptosis induction and chemosensitivity testing, FerroOrange-based intracellular Fe²⁺ quantification, genetic perturbation (shRNA/siRNA), pharmacological NF-κB inhibition, and subcutaneous xenograft models. Spatial transcriptomics validated findings in cancer tissues. Pan-cancer analyses across 31 solid malignant tumor types were performed using GEPIA 2 to assess cross-cancer generalizability. RESULTS: SenCAFs constituted the predominant senescent compartment in the TME, significantly promoting tumor cell proliferation, migration, invasion, and in vivo tumor growth. Multi-omics screening prioritized ferritin heavy chain 1 (FTH1) as the critical effector. Mechanistically, senCAFs upregulated FTH1 to create a stromal iron sink, sequestering microenvironmental Fe2 +, shielding tumor cells from ferroptosis. Disruption of this stromal iron sink by FTH1 silencing not only restored ferroptosis sensitivity but also resensitized tumor cells to cisplatin-induced apoptosis. This iron sink was transcriptionally driven by RELA; targeting RELA abolished FTH1 expression and the senescence phenotype. Spatial transcriptomics validated the FTH1-senCAF-NF-κB axis in situ. Critically, pan-solid tumor analysis also confirmed that upregulation of the RELA-FTH1 axis was associated with poor prognosis and positively correlated with ferroptosis resistance and multiple drug resistance pathways across 31 solid malignancies. CONCLUSIONS: SenCAFs drive therapy resistance by establishing a RELA-FTH1-dependent stromal iron sink. This axis serves as a pan-cancer prognostic and drug resistance biomarker and represents a druggable stromal vulnerability, suggesting that its disruption may resensitize resistant solid malignant tumors to ferroptosis and chemotherapy.