Ferroptosis-Targeted Strategies to Counter Hypoxia- and Acidosis-Associated Immunosuppression in the Tumor Microenvironment.

Abstract

Immunotherapy has transformed cancer treatment, yet its efficacy in solid tumors remains constrained by primary or acquired resistance. Increasing evidence suggests that ferroptosis sensitivity is shaped not only by tumor intrinsic metabolic programs but also by the surrounding microenvironment. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, can directly damage tumor cells and modulate immunity through the release of danger signals and oxidized lipid mediators. At the same time, hypoxia and extracellular acidification, two common features of solid tumors, often reduce ferroptosis susceptibility by reinforcing antioxidant defenses, altering lipid composition, and weakening immune effector function. This review discusses how hypoxia, acidosis, ferroptosis tolerance, and immunosuppression intersect across solid tumors. We summarize the core metabolic and signaling mechanisms involved, compare tumor-specific patterns, and discuss therapeutic strategies that may restore ferroptosis sensitivity, improve immune activity, or both. We also highlight major translational barriers, including spatial heterogeneity, toxicity, limited biomarkers, and the need to distinguish established evidence from emerging concepts. A more precise understanding of the ferroptosis-microenvironment interface may help refine combination strategies for solid tumor immunotherapy.