This study retrieved literature on Ferroptosis and immunity from three databases: Web of Science Core Collection (WoSCC), PubMed, and Scopus. All searches were conducted on the same day to avoid potential bias introduced by daily database updates.

The search strategy employed in the WoS database was formulated as follows: TS=((Ferroptosis) AND (Immune OR Immunity)). The search was restricted to English-language articles and reviews published between January 1, 2012, and August 31, 2025.

For the PubMed database, the search query was defined as: ((Immune[Title/Abstract]) OR (Immunity[Title/Abstract])) AND (Ferroptosis[Title/Abstract]). The following filters were applied to refine the search results: document type (Article or Review), language (English), and publication date (January 1, 2012, to August 31, 2025).

In the Scopus database, the search formula used was: (TITLE-ABS-KEY (Ferroptosis) AND TITLE-ABS-KEY (Immune OR Immunity)). The retrieval was limited to English-language Articles and Reviews, with the publication time frame spanning from 2012 to 2025.

Retrieve the relevant literature and export it in both RefWorks and plain text formats, naming the files as “download-0*.txt”. Utilize CiteSpace 6.4.R1 to perform data deduplication and format conversion. Configure the following parameters: (1) Time slicing: January 1, 2012 – August 31, 2025; set the slice length to “1”. (2) Node types: Select “Author”, “Institution”, and “Keyword” for analysis. (3) Selection criteria: Configure g-index (K = 25), Top N = 50, and Top N%=10.0%. (4) Pruning method: Apply “Pathfinder” and “Pruning sliced network” algorithms. Conduct data preprocessing followed by visual analytics to investigate publication trends, institutional co-occurrence, research collaboration patterns, keyword clustering hotspots, and disciplinary orientations. Generate foundational statistical tables using Excel to enhance data interpretability. Employ VOSviewer to analyze keyword co-occurrence networks based on the exported RefWorks files.

To characterize publication trends in Ferroptosis-immunity research, this study retrieved relevant literature (published January 1, 2012–August 31, 2025) from the WoSCC, PubMed, and Scopus databases via subject term-based searches. Following the exclusion of irrelevant articles per predefined criteria, a total of 3,436 publications were included—consisting of 2,742 research articles and 694 review articles (Figure 2A). Analysis of these trends indicates that Ferroptosis-immunity research had already garnered initial attention prior to 2020. Early studies had established that Ferroptosis occurs in tumor cells and contributes to cancer immunity (14), laying a foundational framework for subsequent investigations. From 2021 to 2025, the annual number of publications increased markedly, solidifying Ferroptosis-immunity as a globally prominent research focus. Two key factors likely drove this sharp growth: first, the widespread adoption of cutting-edge technologies—including gene editing (e.g., CRISPR-Cas9), single-cell sequencing, and nanotechnology—in Ferroptosis-immunity research (15–17); second, significant advances in elucidating the roles of Ferroptosis in tumor immunotherapy and autoimmune diseases (18). These developments have collectively established Ferroptosis-immunity as a research hotspot in the medical field (Figure 2B). Looking forward, as Ferroptosis-immunity research advances—coupled with expanded research funding support and strengthened academic exchanges—the number of publications is projected to keep growing over the next decade. Importantly, this progress may also facilitate the translation of key theoretical findings into clinical practice. For the subject categories of the included literature (Figure 2C), the top five fields were as follows: Oncology (578 publications, 16.8%), Biochemistry Molecular Biology (454 articles, 13.2%), Cell Biology (431 articles, 12.5%), Immunology (421 articles, 12.3%), and Pharmacology Pharmacy (301 articles, 8.8%).

Keywords represent the essence of literature content. Through analytical examination, they can effectively reveal the core intentions of research articles and help identify critical domains and exploration directions in scientific investigations. A visual co-occurrence analysis of the literature on Ferroptosis and immunity in the three databases was performed, and the results were shown in Supplementary Figure 1. The top 30 high-frequency keywords are shown in Supplementary Table 1. We classified 97 keywords with frequency ≥15 occurrences from 3,436 publications. The keywords in VOSviewer are divided into 14 clusters (Supplementary Figure 2), while the results of CiteSpace are divided into four clusters, each of which represents different aspects of the research field. As shown in Figure 7A: the red cluster (Cluster 1) is associated with the core mechanisms of Ferroptosis and underlying diseases, with keywords including Ferroptosis (1,967 occurrences), pyroptosis (114), inflammation (102), apoptosis (100), cell death (92), and oxidative stress (92). The green cluster (Cluster 2) relates to prognostic modeling and biomarker mining of Ferroptosis in cancer, featuring keywords such as prognosis (362), hepatocellular carcinoma (123), cuproptosis (100), immune microenvironment (100), immunity (75), prognostic model (69), and lung adenocarcinoma (66). The blue cluster (Cluster 3) is linked to Ferroptosis-targeted cancer therapeutic strategies, including immunotherapy (344), immunogenic cell death (101), tumor immune microenvironment (51), cancer immunotherapy (42), and chemotherapy (35). The yellow cluster (Cluster 4) involves bioinformatic analysis, genetic signatures, and machine learning, with keywords including immune infiltration (191), bioinformatics (102), biomarker (88), machine learning (84), and bioinformatic analysis (58). Beyond analyzing keywords within these domains, we evaluated the recent research attention received by each cluster. Figure 7B demonstrates that Cluster 3 currently receives comparatively less attention, suggesting that its constituent keywords represent relatively novel research directions. This indicates that research related to therapeutic strategies targeting Ferroptosis in cancer will constitute the core of future research endeavors. To go beyond static cluster analysis and more accurately reveal the dynamic evolutionary trajectory of research hotspots in this field, we further employed the Burst Detection function of CiteSpace software to conduct time-slice analysis on the keywords of literatures published from 2012 to 2025, and identified the top 20 burst terms with the highest intensity (Figure 7C, Supplementary Figure 3). Based on the start and end years of the burst of these keywords, we can clearly observe that the period from 2014 to 2021 belongs to the early foundation-laying and theoretical integration stage: the burst keywords during this period mainly focused on the core mechanisms and basic regulatory pathways of cell death. Examples include “death” (2014-2021), “calreticulin exposure” (2017-2021), “apoptotic cells” (2017-2019), and “nf kappa b” (NF-κB, 2018-2020). The burst periods of these keywords have now ended, indicating that the basic biological framework they represent has matured, integrated into the knowledge cornerstone of this field, and their academic popularity has gradually given way to research directions with greater translational potential. In contrast, the period from 2023 to 2026 is categorized as the recent emerging and frontier expansion stage: the current research frontiers exhibit three major characteristics, namely functionalization, systematization, and technological innovation. The consecutive bursts of “polarization” (2023-2024) and “macrophage polarization” (2024-2026) indicate that the research focus is shifting toward the functional phenotypic regulation of specific immune cells in the tumor immune microenvironment (20). The emergence of “gut microbiota” (2024-2026) as a systemic factor signifies that the research perspective in this field is expanding from the local tumor microenvironment to the distal organ-system crosstalk (21). The burst of “sonodynamic therapy” (2024-2026) reveals that innovative therapeutic strategies for non-pharmaceutical and physical induction of Ferroptosis are gaining widespread attention (22). Dynamic burst analysis demonstrates that the research focus of this field has shifted from the early mechanism discrimination and theoretical foundation-laying to the current precise functional regulation, complex system integration, and innovative technology application.

To our knowledge, this study is the first bibliometric analysis to systematically examine the Ferroptosis-immunity relationship. Furthermore, the methodological design of this study adheres to established guidelines for bibliometric research (23). Three databases—WOSCC, PubMed, and Scopus—were used to retrieve 3,436 relevant publications published between January 1, 2012, and August 31, 2025. These publications encompass contributions from 70 countries, 2,689 institutions, and 19,846 authors. The results reveal a marked upward trend in the number of publications in this field, with a dramatic surge occurring after 2020. This surge is driven primarily by the widespread reporting and validation of several landmark discoveries in the field: notably the in-depth characterization of key Ferroptosis regulatory pathways (e.g., GPX4 and System X_c^⁻), the identification of their synergistic interactions with cancer immunotherapies (e.g., immune checkpoint inhibitors), and the increased global focus on immune and cell death mechanisms spurred by the COVID-19 pandemic (20, 24). Given this momentum, a continued expansion in the number of publications in this area is anticipated.

Among the top 10 most productive countries in this research field, China and the United States stand out as the leading contributors in terms of publication output. This phenomenon stems in part from their substantial investment in scientific research, robust basic research capabilities, large research talent pools, strategic layout in the biomedical sector, and the presence of numerous top-tier research institutions and universities. Notably, despite China’s leading position in publication quantity, its average citations per article lag behind those of other top-producing countries, reflecting a relatively lower overall research quality. This highlights the need for Chinese researchers to prioritize improving the quality of their research outputs.

By analyzing the distribution of article counts across the top 10 research directions (Table 3), the field of Ferroptosis and immunology is anticipated to follow a multifaceted developmental trajectory. Notably, disciplines including Oncology, Biochemistry & Molecular Biology, Cell Biology, and Immunology ranked among the top tiers—underscoring their central role in driving advancements in Ferroptosis-related immunological disease research. As an iron-dependent form of programmed cell death, Ferroptosis exerts a critical influence on tumor initiation, progression, and response to therapeutic interventions. Accumulating studies have confirmed that Ferroptosis not only directly inhibits tumor growth by inducing cancer cell death but also enhances the body’s antitumor immune efficacy: it achieves this by releasing DAMPs that prime antitumor immune responses (25). Accordingly, Ferroptosis research in oncology will remain a focus of intense interest, particularly with respect to the detailed elucidation of its interaction mechanisms with the immune system and the translation of these insights into clinical practice.

In the field of Cell Biology, Ferroptosis has emerged as a process involving intricate intracellular biological mechanisms. Accordingly, Cell Biology, Biochemistry Molecular Biology have established themselves as pivotal disciplines for investigating Ferroptosis, laying a foundational framework for advancing the understanding of its underlying mechanisms and facilitating translational applications.

Immunology emerges as a pivotal interdisciplinary domain in Ferroptosis research, having garnered sustained research attention and exhibited considerable promise in advancing related investigations. Looking ahead, future research directions are likely to encompass two key avenues: on the one hand, targeted regulation of Ferroptosis to augment the cytotoxic activity of immune cells against tumor cells; and on the other hand, harnessing Ferroptosis-elicited immune responses to refine the efficacy of cancer vaccines.

With the growing depth of insight into Ferroptosis mechanisms and ongoing advancements in associated technologies, Ferroptosis research is poised to yield novel insights and enable the development of therapeutic interventions for diverse diseases. Such research avenues not only bear substantial scientific significance but also harbor broad prospects for clinical translation. Leveraging multidisciplinary integration and collaborative innovation, studies focusing on Ferroptosis and immunity are expected to achieve further breakthroughs in the future, ultimately delivering substantial contributions to human health.

Our analysis revealed that “tumor immune microenvironment” (TME) emerges as a high-frequency keyword in recent years, as evidenced by both temporal distribution and keyword clustering analyses (Supplementary Figure 2). The TME is a multifaceted ecosystem encompassing tumor cells, immune cells, stromal cells, and other cellular components. These components do not merely coexist; they engage in intricate crosstalk that exerts profound regulatory effects on tumor growth and progression (26). Notably, Ferroptosis and the TME exhibit intricate interdependencies. During tumorigenesis and progression, rapidly proliferating tumor cells actively remodel the surrounding microenvironment, establishing a supportive niche that promotes their own survival while dampening anti-tumor immune responses. Concurrently, the TME profoundly modulates the Ferroptosis susceptibility of diverse cell populations within it, including tumor cells and immune cells (27). Ferroptosis induction directly dictates tumor cell fate, and its unique metabolic hallmarks (lipid peroxidation and iron dependency) position it as a critical hub connecting tumor biology and immune regulation. On one side, Ferroptosis induction can reshape tumor cell immunogenicity, thereby modulating immune cell function and responsiveness. On the other side, immune cells can actively regulate Ferroptosis in tumor cells via cytokine secretion or direct cell-cell contact (28). It is this multidirectional crosstalk that endows ferroptosis with a complex dual role in tumor immunity, namely pro-tumor and anti-tumor, and the final outcome is heavily dependent on specific cellular contexts and microenvironmental cues. Thus, a thorough dissection of the key molecular mechanisms underlying Ferroptosis, an elucidation of how it mediates immune responses, and a clarification of its dual roles within the TME are imperative for fully deciphering the biological significance of this triangular interplay (Ferroptosis-TME-immunity) and for developing novel Ferroptosis-targeted strategies in tumor immunotherapy.

Based on the analysis of research hotspots and keywords integrated with bibliometric results, we identified that the research direction linking Ferroptosis to oncology has emerged as a prominent topic in recent years. Specifically, oncology accounts for 16.8% of the total publications (ranking as the top research field), and the keyword “immunotherapy” appears 344 times. Herein, we focus on elaborating how the core mechanisms of Ferroptosis regulate tumor immune responses, thereby providing theoretical support for clinical translation.

Ferroptosis, a regulated form of cell death, has emerged as a focal point of interest in tumor research. Beyond functioning as a key intrinsic tumor-suppressive mechanism, it engages in intricate crosstalk with the tumor immune microenvironment to form a complex regulatory network. Notably, this dual role of Ferroptosis in tumor biology manifests in two distinct aspects:On one hand, Ferroptosis inducers (e.g., erastin, RSL3), clinically approved agents (e.g., sorafenib, sulfasalazine, statins, artemisinin), exposure to ionizing radiation, and specific cytokines (e.g., IFNγ, TGFβ1) can effectively induce Ferroptosis, thereby exerting tumor-suppressive effects. On the other hand, Ferroptosis may elicit inflammation-associated immunosuppression within the tumor microenvironment, which in turn promotes tumor progression (29). Thus, a comprehensive understanding of the multifaceted roles of Ferroptosis in tumorigenesis and progression is essential for translating Ferroptosis-targeted therapeutic strategies from preclinical research to clinical practice.

Within the TME, Ferroptosis serves as a pivotal mediator of bidirectional crosstalk between cancer cells and immune cells (As shown in Figure 10). Specifically, cancer cells undergoing Ferroptosis orchestrate antitumor immune responses through the release of context-specific signals; conversely, immune cells can in turn regulate the Ferroptosis susceptibility of cancer cells.

On the one hand, Ferroptosis serves as a critical catalyst for activating anti-tumor immunity. When cancer cells undergo Ferroptosis, they experience membrane rupture driven by lipid peroxidation, releasing DAMPs—notably HMGB1 and ATP. These signaling molecules are recognized by DCs within the TME. Upon sensing DAMPs via receptors such as Toll-like receptor 4 (TLR4), DCs exhibit a marked upregulation in the expression of surface co-stimulatory molecules (e.g., CD80, CD86) and major histocompatibility complex class II (MHC II) molecules. This upregulation promotes DC maturation, enhances their antigen-presenting capacity, and subsequently drives the efficient activation of cytotoxic T lymphocyte (CTL)-mediated anti-tumor responses (79, 80). Notably, oxidized lipids produced during Ferroptosis—e.g., certain hydroxy fatty acid derivatives—can also act as signaling molecules to directly or indirectly regulate immune cell function. Consequently, Ferroptosis in tumor cells induced by radiotherapy, chemotherapy, or agents targeting GPX4/System X_c^⁻ not only exerts direct cytotoxic effects on cancer cells but also reverses the immunosuppressive phenotype of the TME, thereby augmenting the therapeutic efficacy of immune checkpoint inhibitors (e.g., anti-PD-1 antibodies) (81). Importantly, this regulatory axis is not unidirectional: immune cells within the TME can actively exploit Ferroptosis as a weapon to target cancer cells. Activated CD8+ T cells are central to this process: they secrete IFN-γ, which downregulates the expression of SLC7A11—a core component of the System X_c^⁻ transporter on the cancer cell membrane. This downregulation directly impairs cystine uptake by cancer cells, reduces GSH biosynthesis, and inactivates GPX4 activity, thereby significantly increasing cancer cell susceptibility to Ferroptosis (82). This mechanism underscores how adaptive immune responses directly target metabolic vulnerabilities in cancer cells, mediating tumor cell clearance through Ferroptosis induction—a pathway that is critical for tumor elimination by the immune system.

Conversely, the inherent complexity of the TME underpins the double-edged role of Ferroptosis. Under specific contextual conditions, Ferroptosis may either impair immune cells directly or elicit immunosuppressive effects—two outcomes that counteract anti-tumor immunity. For instance, TAMs, particularly M2-polarized TAMs (a phenotype with strong immunosuppressive activity), can protect cancer cells from Ferroptosis. This protective effect is mediated either by secreting metabolites like lactate or through direct cell-cell contact (65). Conversely, certain immunosuppressive cells (e.g., regulatory T cells, Tregs) also exhibit sensitivity to Ferroptosis. Selective induction of Ferroptosis in Tregs can abrogate their suppressive effects on effector T cells, thereby reshaping the immune landscape of the TME. Notably, another dimension of this duality lies in the differential sensitivity of immunosuppressive cells: Tregs, a key mediator of TME immunosuppression, display inherent sensitivity to Ferroptosis. Thus, selective induction of Ferroptosis in Tregs holds potential for mitigating TME immunosuppression and restoring anti-tumor immune responses. Of greater concern, the abundant lipid peroxides and their end products (e.g., 4-HNE) generated during Ferroptosis possess high chemical reactivity. These reactive species can exert direct toxicity on effector immune cells—such as infiltrating CD8+ T cells—inducing functional exhaustion or outright cell death, thereby compromising anti-tumor immunity (54). Beyond immune cell interactions, intercellular crosstalk within the TME further modulates Ferroptosis to favor tumor survival. For example, cancer-associated fibroblasts (CAFs) can support tumor cell resistance to Ferroptosis by two distinct mechanisms: secreting pro-survival signaling molecules or supplying essential metabolites like cysteine (83). Additionally, tumor cells may transfer antioxidant molecules (e.g., GPX4) via exosomes, a process that confers Ferroptosis resistance across the entire tumor cell population rather than individual cells (84). (As shown in Figure 10).

This bibliometric study systematically delineates the fundamental research landscape, hotspots, and evolutionary trends in Ferroptosis and immunity via a visual analytical approach. The findings provide a holistic reference framework for researchers currently engaged in or interested in this field. Notably, this study is not without limitations. First, to enable robust software-driven analysis, data were retrieved exclusively from three databases (WoSCC, PubMed, and Scopus), while other prominent academic platforms such as Google Scholar and Embase were excluded from the analysis. Second, the literature search for this study was conducted up to August 31, 2025. However, papers published between 2024 and 2025 may not have accrued a sufficient number of citations, which could introduce biases into the keyword trend analysis and cutting-edge research identification. Third, limiting the inclusion criteria to English-language publications potentially undermined the comprehensiveness of the literature search. These limitations warrant careful consideration when interpreting the study’s findings. Nevertheless, this work provides valuable insights into the core research areas and emerging frontiers of the Ferroptosis-immunity field.