[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-353156-105":59,"doc-detail-353156-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","tumor-cell-ferroptosis-in-antitumor-immunity-and-immunotherapy-efficacy","Tumor cell ferroptosis in antitumor immunity and immunotherapy efficacy","","Cancer immunotherapy, especially immune checkpoint blockade (ICB), advances treatment across many cancer types, yet a substantial subset shows no clinical response. This gap drives investigation into mechanisms distinguishing efficacy from resistance. Tumor cell–intrinsic pathways, including immune regulatory oncogene activation and immune selection for antigen-loss variants, have gained attention. Emerging data indicate ferroptosis, an iron-dependent lipid-peroxidation death program, supports CD8+ T cell–mediated killing, and some resistant tumors lose ferroptosis sensitivity. 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Journal for ImmunoTherapy of Cancer 2026;14:e014762 . doi:10 . 1136/ jitc-2025-014762  \nAccepted 03 June 2026  \n© Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.  \n1Department of Pathology, The University of Chicago, Chicago, Illinois, USA  \n2Department of Medicine and the Ben May Department of Cancer Research, The University of Chicago, Chicago, Illinois, USA  \nCorrespondence to  \nDr Thomas Gajewski;  \n[tgajewsk@bsd.uchicago.edu](tgajewsk@bsd.uchicago.edu)  \nABSTRACT  \nCancer immunotherapy, particularly immune checkpoint blockade (ICB), has represented a major advancement for the treatment of various cancers. Though ICB has been an effective tool in the clinical management of patients, a significant subset of individuals do not respond clinically. This observation has motivated deeper investigations into the mechanisms of efficacy versus resistance to ICB. Of these, tumor cell-intrinsic mechanisms, such asthe activation of immune regulatory oncogene pathways or immune selection for antigen-loss variants, have been a promising focus of study. Recent evidence has emerged that ferroptosis, a tumor cell-intrinsic cell death pathway, plays an important role in CD8+ T cell-mediated tumor cell killing, and that some resistant tumors have lost sensitivity to this process. Ferroptosis is an irondependent mechanism of cell death that is mediated by the peroxidation of lipids. Tumor cell-intrinsic regulators govern ferroptosis sensitivity and, in turn, can influence the success of immune-mediated tumor control. Here, we discuss the growing understanding of regulation offerroptosis and examine the complex interplay between tumor cell-intrinsic ferroptosis pathways and the host immune response, with an emphasis on how ferroptosis might be leveraged to potentiate immunotherapy efficacy.  \nINTRODUCTION  \nImmunotherapy has transformed cancer treatment. Of these, T cell-based strategies such as immune checkpoint blockade (ICB), which restores the efficacy of host antitumor T cells, or the use of adoptively transferred genetically engineered T cells (eg, chimeric antigen receptor (CAR) T cells and T-cell receptor (TCR)-engineered T cells) have reached success to the point of Food and Drug Administration approval in multiple cancer types.  \nHowever, despite these successes, many patients exhibit primary resistance, and a subset develops secondary resistance. CAR-T therapy is highly effective in hematologic malignancies but shows limited efficacy in solid tumors, highlighting the need to better understand mechanisms driving therapeutic response and resistance.1  \nThe cancer-immunity cycle illustrates key steps governing an anti-tumor immune response.2 Tumor antigens are captured by  \ndendritic cells (DCs), whose activation—partly via the cGAS-STING pathway—induces type I interferons and cytokines. Activated DCs prime tumor-specific T cells in lymph nodes, which differentiate into effector and memory cells and migrate to tumors guided by chemokines such as CXCL9 and CXCL10 (C-X-C motif chemokine ligands 9 and 10) . In the tumor microenvironment (TME), CD8+ T cells recognize tumor cells via TCRmajor histocompatibility complex (MHC) I interactions and can mediate cytotoxicity.3  \nImportantly, many solid tumors have supported the majority of this process up to the point of containing activated tumor antigen-specific T cells in the TME, but without the final step of tumor cell killing. This phenotype has been termed the “T cellinflamed tumor microenvironment” and is at least partially explained by the presence of inhibitory processes that keep those T cells in check. This includes the programmed cell death protein 1 (PD-1)/progra","cbCaisWfW1tEyFT1","https://ap.wps.com/l/cbCaisWfW1tEyFT1","pdf",2100414,11,"English","# Abstract\n# Introduction\n# Mechanisms of T cell-mediated tumor cell death","[{\"question\":\"Why do some patients fail to respond to immune checkpoint blockade (ICB)?\",\"answer\":\"A significant subset of individuals shows clinical non-response, with primary resistance in many patients and secondary resistance developing in others. This motivates research into mechanisms that separate efficacy from resistance.\"},{\"question\":\"What role does ferroptosis play in antitumor immunity?\",\"answer\":\"Ferroptosis is an iron-dependent cell death pathway mediated by lipid peroxidation. Evidence indicates it helps CD8+ T cell–mediated tumor cell killing, and some resistant tumors have lost sensitivity to ferroptosis.\"},{\"question\":\"What are the two major pathways of T cell-mediated tumor cell killing described?\",\"answer\":\"The review highlights (1) a perforin-dependent cytotoxic granule pathway leading to caspase-dependent apoptosis with minimal inflammation, and (2) engagement of death receptors that trigger target cell apoptosis.\"}]","Tumor cell ferroptosis in antitumor immunity and immunotherapy efficacy | PDF",1790103327,28]