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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\u2013microenvironment interface may help refine combination strategies for solid tumor immunotherapy.<\/jats:p>","DOI":"10.1177\/21524971261493449","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:33:37Z","timestamp":1790843617000},"page":"154-165","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ferroptosis-Targeted Strategies to Counter Hypoxia- and Acidosis-Associated Immunosuppression in the Tumor Microenvironment"],"prefix":"10.1177","volume":"28","author":[{"given":"Wanqiu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, China."},{"name":"Shandong Provincial Key Medical and Health Laboratory for Endocrinology and Metabolic Diseases, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, China."},{"name":"Shandong Provincial Key Medical and Health Laboratory for Endocrinology and Metabolic Diseases, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silin","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, China."},{"name":"Shandong Provincial Key Medical and Health Laboratory for Endocrinology and Metabolic Diseases, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7775-2823","authenticated-orcid":false,"given":"Xiaodong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, Weifang, China."},{"name":"Shandong Provincial Key Medical and Health Laboratory for Endocrinology and Metabolic Diseases, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, School of Medicine, Tongji Hospital Affiliated to Tongji University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-022-01998-x"},{"key":"e_1_3_2_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0310"},{"key":"e_1_3_2_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31963-4"},{"key":"e_1_3_2_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.03.019"},{"key":"e_1_3_2_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1705-2"},{"key":"e_1_3_2_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.427"},{"key":"e_1_3_2_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2024.01.013"},{"key":"e_1_3_2_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01332-8"},{"key":"e_1_3_2_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01463-5"},{"key":"e_1_3_2_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.314674.118"},{"key":"e_1_3_2_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-019-0408-1"},{"key":"e_1_3_2_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.901565"},{"issue":"6","key":"e_1_3_2_14_1","first-page":"20240062","article-title":"Activating Ferroptosis of M1 Macrophages: A Novel Mechanism of Asiaticoside Encapsuled in GelMA for Anti-Inflammation in Diabetic Wounds","volume":"5","author":"Cui S","year":"2025","unstructured":"Cui S, , Meng S, , Liu Y, et al. 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