Interplay between natural killer cells and ferroptosis: novel insights in tumor immunity and therapeutic potential

Abstract

Natural killer (NK) cells are essential components of the innate immune system, executing antitumor functions through direct cytotoxicity and cytokine release. Increasing evidence highlights a bidirectional relationship between NK cell activity and ferroptosis, a regulated form of iron-dependent lipid peroxidation, within the tumor microenvironment (TME). NK cell–secreted interferon-gamma can inhibit tumor antioxidant defenses, such as SLC7A11, thereby sensitizing cancer cells to ferroptotic death. In turn, ferroptotic tumor cells release damage-associated molecular patterns that modulate NK cell recruitment and activation. The TME, characterized by hypoxia, elevated adenosine, and immunosuppressive populations, further regulates this interaction by limiting NK cytotoxicity and promoting tumor resistance to ferroptosis. Preclinical studies indicate that combining ferroptosis inducers with NK cell–based immunotherapies yields synergistic antitumor effects. Additionally, genetically engineered NK cells designed to enhance tumor ferroptotic susceptibility represent a promising strategy to overcome immune evasion. This review summarizes recent discoveries on the NK-ferroptosis axis, delineates the molecular and cellular mechanisms governing their crosstalk in the TME, and explores therapeutic opportunities to leverage this pathway for cancer treatment. Understanding this regulatory network could inform the development of innovative immunometabolic interventions to improve current immunotherapy outcomes.

Facts

• NK cells and ferroptosis form a bidirectional regulatory axis in cancer.

• IFN-γ from NK cells promotes tumor ferroptosis by inhibiting SLC7A11.

• Ferroptotic tumor cells release signals that shape NK cell activity.

• Combining ferroptosis inducers with NK cell therapies enhances antitumor efficacy.

Introduction

Ferroptosis, first conceptualized over a decade ago, has recently undergone a paradigm shift from being viewed merely as a metabolic accident to a tightly regulated and context-specific immunogenic death process [1]. In recent years, technological advances such as lipidomics, single-cell transcriptomics, and spatial proteomics have unveiled previously unrecognized layers of ferroptosis control, especially in cancer. Rather than being solely defined by GPX4 inactivation or SLC7A11 inhibition, ferroptosis is now understood to involve intricate lipid remodeling via ACSL4-independent pathways, regulated oxidized phospholipid species, and compartment-specific iron handling [2]. Novel enzymes such as ALOX12/15, PLA2G6, and LPCAT3 now join the classical regulators to orchestrate lipid peroxidation at the subcellular membrane level( [3, 4]). Furthermore, the concept of immunogenic ferroptosis—the idea that ferroptotic cells emit distinct damage-associated molecular patterns (DAMPs) such as oxidized phosphatidylethanolamines (oxPEs) and lipid aldehydes—has introduced a new dimension to our understanding of how ferroptosis interfaces with the immune system. Recent findings also demonstrate that ferroptosis may not be a binary event but can occur in waves, in subpopulations of cancer cells, or in response to spatially restricted microenvironmental cues such as hypoxia, acidosis, or immune infiltration. These advances position ferroptosis not only as a metabolic vulnerability of cancer cells, but also as an orchestrated process that may either silence or activate the surrounding immune contexture.

Natural killer (NK) cells, as innate lymphocytes with cytotoxic potential, are uniquely positioned at the interface of immunity and metabolism [5]. They respond rapidly to cellular stress, viral infection, and malignant transformation, using a repertoire of activating and inhibitory receptors to identify susceptible cells. While traditionally associated with perforin-granzyme-mediated cytolysis and death ligand signaling, recent work has uncovered new layers of NK cell biology that extend into metabolic sensing, mitochondrial adaptation, and immune crosstalk with unconventional forms of cell death. For instance, NK cells directly shape the metabolic landscape of tumor cells through IFN-γ-mediated suppression of antioxidant programs and by reprogramming amino acid and lipid metabolism [6]. Conversely, tumor metabolic states, including redox balance and ferroptotic susceptibility, influence the recruitment, retention, and cytotoxic capacity of NK cells( [7, 8]). These bidirectional signals suggest that NK cells are not passive observers of ferroptosis but may actively regulate, or be regulated by, ferroptotic signaling in tumor cells.

Notably, NK cells are known to induce multiple types of programmed cell death, including apoptosis, pyroptosis, and necroptosis, through the release of perforin, granzymes, and death receptor ligands [9–11]. Ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, represents a mechanistically unique pathway that differs both morphologically and metabolically from these classical routes. Unlike apoptosis, which involves caspase activation and DNA fragmentation, ferroptosis is caspase-independent and primarily driven by dysregulated lipid metabolism and redox imbalance. Pyroptosis and necroptosis, though inflammatory, also do not share the metabolic dependencies seen in ferroptosis [12]. Importantly, tumor cells with high polyunsaturated fatty acid (PUFA) content and iron accumulation are particularly vulnerable to ferroptotic stimuli [13]. This raises the possibility that combining NK cell–mediated cytotoxicity with ferroptosis inducers could synergistically overcome resistance in apoptosis-refractory tumors.

The tumor microenvironment (TME) imposes profound immunometabolic constraints that reshape both cancer and immune cell behavior( [14, 15]). Iron overload, lipid peroxidation, and hypoxic stress coexist with cytokine-mediated immune suppression, creating a niche that paradoxically supports ferroptosis while suppressing anti-tumor immunity [16]. Within this hostile landscape, NK cells are particularly vulnerable due to their reliance on both oxidative phosphorylation and glycolysis to sustain activation, cytotoxicity, and cytokine production [17]. In the TME, ferroptosis of NK cells is also induced by cancer-associated fibroblasts (CAFs) through the regulation of iron metabolism [18]. Furthermore, ferroptotic cancer cells may either release immune-stimulatory signals that promote NK cell recruitment or generate oxidized lipid species that suppress NK cell function [19]. Ferroptotic cancer cells release immunogenic signals, such as high-mobility group box 1 (HMGB1), calreticulin, ATP, and oxidized phospholipids, which promote the recruitment and activation of immune cells including NK cells by enhancing dendritic cell maturation and macrophage phagocytosis( [20, 21]). Conversely, the accumulation of oxidized lipid species in the tumor milieu may suppress NK cell function and contribute to immune evasion [22]. These opposing effects indicate that the NK–ferroptosis axis is finely tuned and context-dependent. Understanding this complex crosstalk is not only critical for decoding immune evasion in tumors but also presents an opportunity to develop combination therapies that leverage ferroptosis inducers to restore or enhance NK cell-mediated anti-tumor immunity. In this review, we summarize current knowledge on the crosstalk between ferroptosis and NK cells in cancer. We focus on how ferroptosis in tumor cells affects NK cell-mediated immunity, how NK cells regulate tumor ferroptosis sensitivity, and the role of the tumor microenvironment in modulating this interaction. Finally, we discuss potential therapeutic implications of targeting the NK-ferroptosis axis to enhance cancer immunotherapy.

Mechanisms of ferroptosis induction and regulation

Lipid peroxidation as the core driver of ferroptosis

Ferroptosis is a distinct form of regulated cell death driven by the iron-dependent accumulation of lipid peroxides in cellular membranes( [23, 24]) (Fig. 1). The peroxidation of polyunsaturated fatty acids (PUFAs), particularly arachidonic acid (AA) and adrenic acid (AdA), incorporated into membrane phospholipids, constitutes the central biochemical event triggering ferroptosis. The enzymes Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) and Lysophosphatidylcholine Acyltransferase 3 (LPCAT3) facilitate the incorporation of PUFAs into phosphatidylethanolamine (PE), enhancing the pool of peroxidizable lipids( [25, 26]). Lipoxygenases (LOXs), a family of iron-containing enzymes, catalyze the selective oxidation of PUFA-PEs to generate lipid hydroperoxides, thereby amplifying the lipid peroxidation cascade. In addition, non-enzymatic free radical chain reactions contribute to lipid peroxide accumulation once initiated. The susceptibility of cells to ferroptosis is highly dependent on the balance between lipid peroxide production and detoxification [27]. Recent studies have identified that altering the lipid composition of membranes, such as increasing PUFA content, sensitizes cells to ferroptosis, while monounsaturated fatty acids (MUFAs) have protective effects by reducing lipid peroxidation. This dynamic highlights the critical role of membrane lipid remodeling enzymes in ferroptosis regulation.

Fig. 1.

Lipid metabolic pathway driving ferroptosis through polyunsaturated phospholipid peroxidation. Polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and adrenic acid (AdA), are generated intracellularly and first activated by Acyl-CoA synthetase long-chain family member 4 (ACSL4) to form PUFA-CoA. These activated PUFAs are then esterified into membrane phosphatidylethanolamine (PE) by Lysophosphatidylcholine acyltransferase 3 (LPCAT3), producing peroxidation-susceptible PUFA-PE species. Lipoxygenases (LOXs), iron-containing enzymes, catalyze the oxidation of PUFA-PEs to lipid hydroperoxides (PUFA-PE-OOH), and non-enzymatic free radical chain reactions further amplify lipid peroxidation. Accumulation of PUFA-PE-OOH disrupts membrane integrity, triggering ferroptotic cell death. Saturated fatty acyl-CoAs (SFA-CoA) can be desaturated by Stearoyl-CoA desaturase 1 (SCD1) to form monounsaturated fatty acids (MUFAs), which are incorporated into membrane phospholipids and reduce susceptibility to lipid peroxidation. In addition, cholesterol biosynthesis intermediates contribute to ferroptosis regulation: Zymosterol is converted to 7-dehydrocholesterol (7-DHC) by SC5D, which can protect membranes from peroxidation, and 7-DHC is further reduced to cholesterol by DHCR7. Collectively, these pathways balance lipid peroxidation and membrane protection, determining cellular sensitivity to ferroptosis

A recent CRISPR-Cas9 screen identified that enzymes in distal cholesterol biosynthesis regulate ferroptosis by controlling levels of 7-dehydrocholesterol (7-DHC), which protects membranes from lipid peroxidation. Inhibiting cholesterol synthesis enzymes like EBP induces ferroptosis and suppresses tumor growth, while increasing 7-DHC promotes metastasis and protects against ischemia-reperfusion injury, revealing a novel metabolic axis for ferroptosis modulation( [28, 29]).

Iron metabolism and its pivotal role in ferroptosis

Iron is indispensable for ferroptosis due to its unique ability to catalyze the generation of reactive oxygen species (ROS) through the Fenton reaction, which converts hydrogen peroxide (H₂O₂) into highly reactive hydroxyl radicals (•OH). These radicals initiate and propagate lipid peroxidation, damaging polyunsaturated fatty acids in cellular membranes and ultimately triggering ferroptotic cell death [30] (Fig. 2).

Fig. 2.

Iron metabolic pathway in the regulation of ferroptosis. Transferrin-bound ferric iron (Fe³⁺) is imported into cells via Transferrin receptor 1 (TFRC)-mediated endocytosis. Within endosomes, Fe³⁺ is reduced to ferrous iron (Fe²⁺) and released into the cytoplasm by Divalent metal transporter 1 (DMT1), contributing to the labile iron pool (LIP). Excess Fe²⁺ is sequestered by Ferritin (composed of FTH1 and FTL subunits) in an inert ferric form. Iron export is mediated by Ferroportin (FPN). Ferritinophagy, a selective autophagy process mediated by Nuclear receptor coactivator 4 (NCOA4), delivers ferritin to lysosomes for degradation, releasing Fe²⁺ back into the LIP. Elevated LIP participates in the Fenton reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + •OH + OH⁻), generating hydroxyl radicals that drive lipid peroxidation. Mitochondria import Fe²⁺ via Mitoferrin-1 (MFRN1) and Mitoferrin-2 (MFRN2) for heme and iron–sulfur cluster biosynthesis, but excessive mitochondrial iron promotes reactive oxygen species (ROS) production through the electron transport chain, further sensitizing cells to ferroptosis

Cellular iron homeostasis is tightly controlled by a network of proteins that regulate iron uptake, storage, utilization, and export to prevent toxic iron overload or deficiency( [31, 32]). Transferrin receptor 1 (TFRC) is the main mediator of iron uptake; it binds transferrin-bound ferric iron (Fe³⁺) and facilitates its internalization through receptor-mediated endocytosis. Inside endosomes, ferric iron is reduced to ferrous iron (Fe²⁺) and transported into the cytoplasm via divalent metal transporter 1 (DMT1). The labile iron pool (LIP) in the cytoplasm consists of redox-active ferrous iron capable of participating in Fenton chemistry [33]. Excess intracellular iron is safely sequestered by ferritin, a multi-subunit protein complex composed of ferritin heavy chain (FTH1) and light chain (FTL), which stores iron in an inert ferric form (Fe³⁺), preventing iron-mediated oxidative damage. Ferroportin (FPN, encoded by SLC40A1) is the only known cellular iron exporter, responsible for transporting iron out of cells to maintain systemic and cellular iron balance [34]. Dysregulation in any of these pathways—such as increased TFRC expression, decreased ferritin levels, or reduced ferroportin activity—can elevate the cytosolic LIP, heightening ROS production and sensitizing cells to ferroptosis. A critical process linking iron metabolism to ferroptosis is ferritinophagy, a selective form of autophagy that degrades ferritin and releases stored iron back into the LIP. This process is mediated by nuclear receptor coactivator 4 (NCOA4), which binds ferritin and targets it for lysosomal degradation [35]. Upregulation of ferritinophagy increases free iron availability, amplifying ROS generation and promoting ferroptotic cell death. Conversely, inhibition of ferritinophagy limits iron release and confers resistance to ferroptosis. Emerging evidence underscores the role of mitochondrial iron metabolism in ferroptosis regulation( [36, 37]). Mitochondria are the major site of cellular iron utilization, essential for the biosynthesis of iron-sulfur clusters and heme groups, and are a significant source of endogenous ROS through the electron transport chain. Mitochondrial iron import is mediated by mitoferrin-1 and mitoferrin-2, while mitochondrial iron export mechanisms are less well understood but crucial for maintaining mitochondrial iron homeostasis [38]. Disruption of mitochondrial iron balance leads to excessive mitochondrial ROS production, lipid peroxidation, and heightened ferroptosis sensitivity.

Antioxidant defense systems counteracting ferroptosis

To maintain redox balance and prevent uncontrolled lipid peroxidation, cells deploy robust antioxidant systems. Glutathione Peroxidase 4 (GPX4) is the principal enzyme that reduces lipid hydroperoxides to non-toxic lipid alcohols, utilizing glutathione (GSH) as a reducing cofactor [39]. The synthesis of GSH depends on intracellular cysteine levels, which are maintained primarily through the cystine/glutamate antiporter system Xc–, encoded by SLC7A11. Inhibition of system Xc– or depletion of GSH abrogates GPX4 activity, leading to ferroptosis. Recently, the identification of Ferroptosis Suppressor Protein 1 (FSP1, also known as AIFM2) has expanded the paradigm of ferroptosis regulation. FSP1 functions independently of GPX4 by reducing coenzyme Q10 (CoQ10) to its antioxidant form, ubiquinol, which traps lipid radicals and inhibits lipid peroxidation [40]. This discovery reveals an additional layer of ferroptosis resistance and opens new avenues for therapeutic intervention. In addition, the GTP Cyclohydrolase 1 (GCH1)-Tetrahydrobiopterin (BH4) axis has been recently identified as another potent ferroptosis defense mechanism [41]. BH4 acts as a radical-trapping antioxidant that protects lipids from peroxidation independently of GPX4 and FSP1, contributing to ferroptosis resistance especially in cancer cells.

Moreover, dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme involved in pyrimidine synthesis, plays a critical role in protecting mitochondria from ferroptosis [42]. DHODH reduces CoQ to ubiquinol within mitochondria, limiting mitochondrial lipid peroxidation and ferroptotic cell death under GPX4 deficiency [43]. Finally, recent studies have also highlighted the role of metallothioneins (MTs), small cysteine-rich metal-binding proteins, in ferroptosis suppression [44]. MTs can scavenge reactive oxygen species and chelate labile iron, thus limiting iron-mediated lipid peroxidation and protecting against ferroptosis [45]. Together, these diverse antioxidant systems form a complex network that tightly regulates ferroptosis, offering multiple potential targets for therapeutic modulation.

Emerging regulators and signaling pathways influencing ferroptosis

Beyond classical lipid peroxidation and iron metabolism, several transcription factors and signaling pathways have been implicated in modulating ferroptosis sensitivity. Nuclear Factor Erythroid 2–Related Factor 2 (NRF2) acts as a master regulator of cellular antioxidant responses, upregulating genes involved in glutathione synthesis, iron storage, and ROS detoxification, thereby conferring resistance to ferroptosis [46]. Conversely, the tumor suppressor p53 exhibits dual roles in ferroptosis regulation depending on cellular context, either promoting ferroptosis by repressing SLC7A11 expression or inhibiting it via p21 induction [47]. Metabolic rewiring, including alterations in glutaminolysis and the tricarboxylic acid (TCA) cycle, also impacts ferroptosis susceptibility by modulating cellular redox status and energy metabolism [48]. Furthermore, cellular processes such as autophagy and membrane repair mechanisms intersect with ferroptosis pathways, adding complexity to its regulation.

Ferroptosis in tumor cells modulates NK cell-mediated immunity

Ferroptosis exposes NK-activating signals and reduces inhibitory ligands

Ferroptotic stress induces alterations in the tumor cell surface that facilitate enhanced recognition and activation of NK cells (Fig. 3). A pivotal mechanism underlying this process is the upregulation of NKG2D ligands, including MICA, MICB, and members of the ULBP family. Ferumoxytol-induced ferroptosis in prostate cancer cells enhances NK cell cytotoxicity by upregulating NKG2D ligands such as ULBPs, promoting IFN-γ release and degranulation [49]. This synergy suggests ferroptosis boost NK cell–mediated antitumor immunity. In addition, ferroptosis induced in tumor cells by prostate-specific membrane antigen (PSMA)-targeted chimeric antigen receptor-engineered natural killer (CAR-NK) cells enhanced their anti-tumor immune activity, primarily through interferon-gamma (IFN-γ)–mediated mechanisms [50]. This suggests that ferroptosis not only contributes to direct tumor cell death but also amplifies NK cell–driven immunotherapy efficacy in castration-resistant prostate cancer.

Fig. 3.

Ferroptosis in tumor cells modulates NK cell–mediated immunity through multiple interconnected mechanisms. (A) Ferroptotic stress upregulates NKG2D ligands (MICA/B, ULBPs) on tumor cells, enhancing NK cell recognition and activation, resulting in increased IFN-γ release and cytotoxicity. (B) Ferroptotic tumor cells release immunomodulatory signals such as DAMPs (ATP, HMGB1) and lipid peroxidation byproducts (4-HNE), which influence NK cell recruitment and function within the tumor microenvironment. (C) Oxidative DNA damage product 8-OHG from ferroptotic tumor cells activates the cGAS–STING pathway in tumor-associated macrophages, promoting type I interferon production and inflammatory cytokines that facilitate NK cell infiltration. Concurrently, lipid peroxidation imposes metabolic stress on NK cells, which can be alleviated by NRF2 antioxidant pathway activation to restore NK effector functions. (D) Schematic summarizing the dual role of ferroptosis in modulating NK cell immunity: early ferroptotic signals promote NK recruitment and activation, whereas prolonged ferroptotic stress induces NK metabolic dysfunction and impaired cytotoxicity, highlighting a complex regulatory balance in the tumor microenvironment

Ferroptotic cells release Immunomodulatory signals that influence NK recruitment and activity

Ferroptotic tumor cells are confirmed to release DAMPs like ATP and HMGB1, with HMGB1 secretion occurring via autophagy-dependent pathways during ferroptosis inducers such as erastin, RSL3, and FIN56—though most evidence comes from macrophage studies [51]. Additionally, lipid peroxidation byproducts such as 4-hydroxynonenal (4-HNE) accumulate during ferroptosis and have been shown to impair immune cell function: for instance, 4-HNE treatment of K562 target cells significantly reduced their susceptibility to natural killer cell–mediated cytotoxicity [52]. While direct proof linking these factors to NK cell activation remains limited, their documented roles in modulating innate immune responses support a context-dependent immunoregulatory impact of ferroptosis-derived signals.

Ferroptotic stress reprograms TME to regulate NK cell access

Beyond direct ligand and metabolite signaling, ferroptotic stress reshapes the broader tumor immune landscape, impacting NK cell access and function. For example, in pancreatic cancer models, GPX4 depletion or high-iron diets lead to the release of oxidative DNA damage–derived 8-hydroxydeoxyguanosine (8-OHG) from ferroptotic tumor cells, which activates the cGAS–STING pathway in tumor-associated macrophages [53]. This triggers type I interferon production and pro-inflammatory cytokines that promote macrophage recruitment and polarization, thereby indirectly modulating NK cell behavior via enhanced chemokine expression and immune cell cross-talk. Concurrently, ferroptotic tumor cells generate lipid peroxidation products that directly influence tumor-infiltrating NK cells. Elevated lipid peroxidation within NK cells is linked to metabolic dysregulation and impaired cytotoxic function in the tumor microenvironment. Activation of the NRF2 antioxidant pathway in NK cells alleviates this oxidative stress, restoring metabolic homeostasis and enhancing antitumor effector functions [7]. Ferroptosis occurs in spatially heterogeneous tumor microenvironments shaped by variations in oxygen tension, nutrient availability, and lipid composition [54]. Early ferroptotic tumor cells release DAMPs and chemokines that may promote NK cell recruitment and activation, though the precise temporal dynamics remain to be fully elucidated. Together, these mechanisms illustrate how ferroptosis-associated oxidative stress in the tumor microenvironment acts as a double-edged sword, both promoting NK cell recruitment through immune signaling and imposing metabolic constraints that limit NK cell cytotoxicity.

NK cells influence ferroptosis sensitivity in tumor cells

NK-derived cytokines sensitize tumor cells to ferroptosis

NK cells contribute to anti-tumor immunity not only through direct cytotoxic mechanisms but also by shaping tumor cell vulnerability via cytokine secretion. Among these, interferon-gamma (IFN-γ) is the most extensively characterized and has been shown to enhance tumor cell susceptibility to ferroptosis by disrupting redox homeostasis (Fig. 4). Mechanistically, IFN-γ suppresses the expression of key components of the cystine/glutamate antiporter system Xc⁻—namely SLC7A11 and SLC3A2—thereby impairing cystine uptake and downstream glutathione (GSH) synthesis( [55, 56]). This reduction in antioxidant capacity leads to elevated lipid peroxidation and renders tumor cells highly sensitive to ferroptosis inducers such as Erastin and RSL3. Although this mechanism was originally described in the context of CD8⁺ T cells, it likely extends to NK cells, which also produce high levels of IFN-γ in the tumor microenvironment [57]. While IFN-γ is the most well-established NK-derived cytokine involved in ferroptotic sensitization, tumor necrosis factor-alpha (TNF-α) may also contribute to ferroptosis indirectly through pro-inflammatory pathways. TNF-α can activate NF-κB signaling and promote nitric oxide production, which has been implicated in mitochondrial dysfunction and increased ROS accumulation.

Fig. 4.

NK cells enhance ferroptosis sensitivity in tumor cells through cytokine secretion and granule-mediated oxidative stress. (A) IFN-γ secreted by activated NK cells suppresses expression of the cystine/glutamate antiporter system Xc⁻ (comprising SLC7A11 and SLC3A2), thereby reducing cystine uptake and glutathione (GSH) synthesis. The resulting depletion of antioxidant defenses leads to elevated lipid peroxidation and increased susceptibility to ferroptosis in the presence of inducers such as erastin or RSL3. (B) NK cells induce oxidative stress in tumor cells through perforin-mediated pore formation and granzyme B–mediated mitochondrial damage, resulting in ROS accumulation. This enhances the ferroptotic vulnerability of tumor cells, particularly under conditions of impaired redox buffering

NK perforin and granzyme pathways promote ferroptosis via oxidative stress

NK cells eliminate tumor cells primarily via cytolytic granules releasing perforin and granzymes, which classically induce apoptosis through caspase activation. Perforin forms pores on target cell membranes, allowing granzyme B entry to trigger mitochondrial outer membrane permeabilization (MOMP) and apoptosis [58]. Mitochondrial dysfunction resulting from granzyme B activity can lead to increased ROS generation, a key mediator of ferroptosis [59]. While direct experimental evidence linking NK cell granule-mediated cytotoxicity to ferroptosis is limited, the oxidative stress induced by these pathways may sensitize tumor cells to ferroptotic death, especially under conditions of impaired antioxidant defense. Further research is warranted to elucidate whether NK cell-mediated mitochondrial damage and ROS production facilitate ferroptosis in tumor cells, possibly through disruption of iron homeostasis and lipid peroxidation pathways.

NK cells remodel tumor metabolism to enhance ferroptosis susceptibility

NK cells profoundly influence the tumor microenvironment by secreting cytokines such as IFN-γ and TNF-α, which modulate various metabolic pathways within tumor cells that are critical for ferroptosis regulation (Fig. 5). IFN-γ, in particular, has been extensively studied for its capacity to disrupt tumor antioxidant defenses, thereby sensitizing tumor cells to ferroptotic cell death. Functionally, IFN-γ exerts its effects by suppressing the expression of critical components of the cystine/glutamate antiporter system Xc⁻, including SLC7A11, which results in reduced cystine uptake, depletion of intracellular glutathione, and increased lipid peroxidation, thereby enhancing tumor cell susceptibility to ferroptosis [57]. Beyond its impact on cystine metabolism, IFN-γ also modulates tumor cell lipid metabolism, which is pivotal in ferroptosis susceptibility. Lipid peroxidation preferentially targets polyunsaturated fatty acids (PUFAs) incorporated into membrane phospholipids( [23, 24]). The enzyme ACSL4 facilitates the esterification of PUFAs into phospholipids, promoting lipid peroxidation and ferroptotic death. While direct evidence for NK cell-mediated regulation of ACSL4 expression in tumor cells is currently limited, ACSL4 remains a critical determinant of ferroptosis sensitivity and a potential target for immune-metabolic interactions [25]. Similarly, stearoyl-CoA desaturase 1 (SCD1), an enzyme responsible for converting saturated fatty acids into monounsaturated fatty acids (MUFAs), acts as a protective factor against ferroptosis by reducing the availability of PUFAs for peroxidation [60]. Inhibition or downregulation of SCD1 increases PUFA in membranes and enhances ferroptosis susceptibility. Although the precise role of NK cells in modulating SCD1 expression is not yet fully elucidated, inflammatory cytokines such as IFN-γ and TNF-α have been shown in other cellular contexts to repress SCD1, suggesting a plausible pathway for NK cell-driven metabolic reprogramming that favors ferroptosis [61]. In addition to lipid metabolism, glutamine metabolism constitutes a critical metabolic axis influencing ferroptosis sensitivity. Glutamine serves as a precursor for glutathione synthesis, thereby sustaining cellular antioxidant defenses essential for preventing lipid peroxidation [62]. Restriction of glutamine availability or pharmacological inhibition of glutaminolysis enzymes such as glutaminase (GLS) has been demonstrated to deplete intracellular glutathione pools, enhancing susceptibility to ferroptosis in various cancer models [63]. Although the direct impact of NK cell-secreted factors on tumor glutamine metabolism remains largely unexplored, it is plausible that NK cells modulate the tumor microenvironment through cytokine secretion, thereby indirectly affecting tumor metabolic pathways and redox homeostasis.

Fig. 5.

NK cells remodel tumor metabolism to enhance ferroptosis susceptibility. NK cells secrete cytokines such as IFN-γ and TNF-α, which modulate key metabolic pathways in tumor cells governing ferroptosis sensitivity. IFN-γ downregulates system Xc⁻ by suppressing SLC7A11, leading to reduced cystine uptake, GSH depletion, and increased lipid peroxidation. NK cytokines may also suppress SCD1, decreasing MUFA synthesis and increasing PUFA availability for peroxidation. ACSL4 facilitates PUFA incorporation into membrane phospholipids, promoting ferroptosis. Glutamine metabolism supports GSH synthesis via GLS, maintaining antioxidant defenses. While direct NK regulation of glutamine metabolism is unclear, cytokine-mediated tumor microenvironment modulation may indirectly influence this pathway. Overall, NK-induced metabolic reprogramming sensitizes tumor cells to ferroptosis, highlighting a potential synergistic strategy for cancer immunotherapy

NK cell-tumor interactions activate ferroptosis-related transcriptional programs

Interactions between NK cells and tumor cells can induce transcriptional changes that potentially modulate ferroptosis sensitivity. While single-cell RNA sequencing (scRNA-seq) studies have begun to unravel the complexity of tumor-immune interactions, direct evidence linking NK cell activity to ferroptosis-associated gene expression in adjacent tumor cells remains limited and warrants further investigation. IFN-γ, a major cytokine secreted by NK cells, induces transcription factors such as IRF1, which has been shown to repress SLC7A11 expression and promote ferroptosis in tumor cells [57].

Emerging evidence highlights the potential role of the stress-responsive transcription factor ATF3 in ferroptosis regulation. ATF3 can be induced by cytokine-mediated stress signals and has been reported to suppress SLC7A11 expression, thereby reducing cystine uptake and glutathione synthesis, sensitizing tumor cells to lipid peroxidation and ferroptotic death( [64, 65]). Although direct evidence of NK cell-mediated ATF3 activation in tumor cells is currently lacking, it is plausible that NK cell-derived cytokines such as IFN-γ and TNF-α could indirectly trigger ATF3-dependent transcriptional programs, thereby linking immune signaling to ferroptosis susceptibility.

In addition, nuclear factor erythroid 2–related factor 2 (NRF2) signaling acts as a critical regulator of antioxidant defenses in tumor cells. Although NK cell-mediated activation of NRF2 has not been directly demonstrated, NRF2 is known to have a dual role—initially promoting antioxidant capacity, but under sustained stress conditions, contributing to ferroptosis sensitization [66]. While selective autophagy of ferritin (ferritinophagy) via NCOA4 is a recognized mechanism promoting ferroptosis [67], evidence for NK cells directly modulating this pathway is currently lacking.

Ferroptosis in NK cells: a double-edged sword in tumor immunity

NK cells are critical innate immune effectors that mediate antitumor immunity and antiviral defense. However, recent studies reveal that ferroptosis—a regulated, iron-dependent form of cell death—plays a dual role in modulating NK cell function within the TME, acting both as a threat to NK cell viability and a potential target for enhancing NK-based therapies (Fig. 6).

Fig. 6.

Ferroptosis regulation in NK cells within the tumor microenvironment. (A) Tumor cells release L-kynurenine, which enters NK cells via amino acid transporters (e.g., LAT1). Inside NK cells, L-kynurenine induces reactive oxygen species (ROS) generation and lipid peroxidation, promoting ferroptosis and leading to partial NK cell death. NK cells counteract this by upregulating glutathione peroxidase 4 (GPX4), an antioxidant enzyme that inhibits lipid peroxidation and ferroptosis, thereby maintaining cell survival and function. (B) The commensal bacterium Brevibacillus parabrevis promotes lipolysis, generating acetyl-CoA that enters the NK cell nucleus and induces acetylation of the transcription factor RORγt. This acetylation activates the ubiquitin ligase NEDD4L, which mediates degradation of iron transporters in the cytoplasm, lowering intracellular iron levels and reducing NK cell ferroptosis sensitivity. (C) Invariant natural killer T (iNKT) cells, a specialized subset of NK family lymphocytes, exhibit impaired function and survival upon GPX4 deficiency. Loss of GPX4 leads to increased lipid peroxidation, mitochondrial stress, decreased production of interferon-gamma (IFN-γ), and reduced cell viability, highlighting the critical role of GPX4 in maintaining iNKT cell homeostasis and antitumor immunity

Ferroptosis as a mechanism of NK cell dysfunction and depletion

Tumor-derived metabolites can induce ferroptosis in NK cells, contributing to their functional impairment and numerical reduction in tumors. For example, L-kynurenine, produced by gastric cancer cells, triggers ferroptotic death in NK cells through an aryl hydrocarbon receptor (AHR)-independent mechanism, leading to NK cell depletion within the TME [68]. This ferroptosis-mediated loss of NK cells weakens innate immune surveillance and facilitates tumor progression. Correspondingly, overexpression of glutathione peroxidase 4 (GPX4)—a key ferroptosis suppressor—in NK cells confers resistance to ferroptotic death, suggesting a promising strategy to bolster NK cell survival and enhance immunotherapeutic efficacy [68]. In hepatocellular carcinoma, inhibition of NK cell ferroptosis via intratumoral administration of Brevibacillus parabrevis enhances antitumor immunity [69]. Mechanistically, B. parabrevis induces lipolysis and subsequent acetyl-CoA production, which acetylates RORγt (RORC). This modification promotes NEDD4L-mediated ubiquitination and degradation of iron transporters, thereby reducing ferroptotic susceptibility in NK cells and preserving their cytotoxic functions and metabolic adaptability. Similarly, GPX4 protects invariant natural killer T (iNKT) cells from ferroptosis by mitigating lipid peroxidation. GPX4 deficiency in iNKT cells results in lipid peroxide accumulation, mitochondrial oxidative stress, impaired IFN-γ production, and diminished survival, highlighting ferroptosis as a critical regulator of NK cell homeostasis and effector activity [70].

Ferroptosis-associated lipid peroxidation as a functional regulator of NK cells

Beyond ferroptotic death, sublethal lipid peroxidation can also induce metabolic dysfunction and exhaustion in NK cells within the TME. Elevated lipid peroxidation on NK cell plasma membranes correlates with impaired cytotoxicity and decreased effector cytokine production. Activation of the NRF2 antioxidant pathway effectively reverses this metabolic dysregulation and functional exhaustion, restoring NK cell antitumor activity in vivo [7]. Intriguingly, ferroptosis inducers such as Erastin can promote lipid peroxidation in human peripheral blood mononuclear cells (PBMCs) in vitro, facilitating their proliferation and differentiation towards NK cells and B cells [71]. This suggests that ferroptotic signaling may have context-dependent roles, not only impairing but also potentially modulating immune cell development.

Therapeutic implications: balancing ferroptosis to enhance NK cell-based cancer immunotherapy

Given the dual nature of ferroptosis in NK cells, therapeutic strategies must carefully balance inducing ferroptosis in tumor cells while protecting NK cells from ferroptotic death. NK cell-derived IFN-γ, for instance, potently downregulates tumor cell expression of SLC3A2 and SLC7A11, key components of the cystine/glutamate antiporter system Xc⁻, thereby promoting ferroptosis in cancer cells [72]. This highlights the potential of leveraging NK cell function to sensitize tumors to ferroptosis-based therapies. Simultaneously, preserving NK cell viability and function by mitigating ferroptosis—through GPX4 upregulation, NRF2 activation, or microbial modulation of iron metabolism—may enhance the efficacy of NK cell-mediated tumor clearance. Further elucidation of ferroptosis regulatory networks in NK cells is essential for designing combined immunometabolic therapies that exploit this double-edged sword to maximize antitumor immunity.

Tumor microenvironment regulates NK cell and ferroptosis crosstalk in cancer

Metabolic constraints in the TME suppress NK function and ferroptosis sensitivity

TME imposes significant metabolic challenges that concurrently impair NK cell function and enhance tumor resistance to ferroptosis, thereby facilitating immune evasion and tumor progression [73]. Nutrient deprivation, hypoxia, and accumulation of immunosuppressive metabolites create a hostile milieu that inhibits NK cell cytotoxicity and cytokine production( [74, 75]). These metabolic stresses also drive tumor cells to adapt by enhancing their antioxidant defenses, increasing resistance to ferroptosis-induced cell death. Understanding how metabolic constraints shape the interplay between NK cells and ferroptosis within the TME is crucial for developing effective combinatorial therapies that restore NK cell activity and sensitize tumors to ferroptotic killing.

Adenosine is a key immunosuppressive metabolite generated in hypoxic TMEs by ectonucleotidases CD39 and CD73, which hydrolyze extracellular ATP into adenosine [76]. Adenosine engages the A2A receptor on NK cells, suppressing their cytotoxicity by reducing IFN-γ secretion and downregulating perforin and granzyme B expression [77] (Fig. 7). Although direct evidence linking adenosine signaling to altered ferroptosis sensitivity via SLC7A11 regulation in tumor cells remains limited, the immunosuppressive impact on NK cells may indirectly influence ferroptosis susceptibility through diminished IFN-γ secretion. In addition, lactate is a major metabolic byproduct of aerobic glycolysis in tumors, lactic acid accumulation, driven by elevated LDHA in tumors, impairs NK cell function by inhibiting NFAT activation and reducing IFN-γ production, thereby suppressing antitumor immunity [78]. Beyond classical metabolites, tumor-derived L-kynurenine has been shown to directly induce ferroptosis in NK cells via an AHR-independent mechanism [68]. In gastric cancer, L-kynurenine triggers ferroptotic death in NK cells, leading to immune depletion in the TME. Overexpression of GPX4 in NK cells protects them from ferroptosis and restores cytotoxicity, suggesting potential for therapeutic enhancement of NK cell survival. In addition, CAFs can promote NK cell ferroptosis through metabolic reprogramming. CAFs increase iron efflux and upregulate NCOA4-mediated ferritinophagy in NK cells, leading to labile iron accumulation and lipid peroxidation [18]. This CAF-induced ferroptosis impairs NK cell viability and function, weakening immune control of tumors. Together, these metabolites form a multifaceted metabolic checkpoint within the TME that dampens NK cell effector functions and strengthens tumor cell defenses against ferroptosis. Targeting these pathways may restore NK cell activity and sensitize tumors to ferroptosis, offering a dual approach for cancer therapy.

Fig. 7.

Adenosine–A2A receptor signaling mediates NK cell immunosuppression and ferroptosis resistance in the tumor microenvironment. Tumor cells overexpress ectonucleotidases CD39 and CD73, which sequentially hydrolyze extracellular ATP/ADP to AMP and adenosine. Accumulated adenosine binds to the A2A receptor on NK cells, activating the Gs protein (Gα, Gβ, and Gγ subunits) and stimulating adenylate cyclase (AC) to increase intracellular cAMP levels. Elevated cAMP activates protein kinase A (PKA), which phosphorylates CREB and modulates transcriptional programs via CRE and NF-κB binding sites, leading to increased IL-10 production and reduced IFN-γ expression, thereby suppressing NK cell cytotoxicity. In parallel, tumor-derived lactate—exported via monocarboxylate transporters (MCT)—contributes to lipid peroxidation and ferroptosis in susceptible cells. However, adenosine–PKA signaling upregulates antioxidant pathways, conferring ferroptosis resistance in NK cells. Together, these mechanisms promote immune evasion in the tumor microenvironment

Immunosuppressive cells and hypoxia reprogram NK-ferroptosis interplay

The TME exerts a profound influence on both immune surveillance and ferroptosis susceptibility. Hypoxia-inducible factor 1-alpha (HIF-1α), stabilized under low oxygen conditions, induces the expression of ferroptosis resistance genes in tumor cells, including SLC7A11 and GPX4, and enhances lipid droplet biogenesis to buffer against lipid peroxidation( [79, 80]). Concurrently, hypoxia impairs NK cell cytotoxic function by reducing the expression of activating receptors such as NKG2D and NKp30, suppressing IFN-γ production, and promoting an exhausted NK cell phenotype [81]. Hypoxia also impairs NK cell antitumor function by inducing HIF-1α, which suppresses activation markers and effector molecules [82]. In contrast, HIF-1α inhibition enhances NK cell cytotoxicity via IL-18–mediated NF-κB activation [82]. These dual effects make hypoxia a key metabolic and immunologic barrier that simultaneously undermines ferroptotic cell death and innate immune responses.

Physical and structural barriers modulate NK infiltration and ferroptosis induction

Dense extracellular matrix (ECM) deposition, primarily by cancer-associated fibroblasts, creates physical barriers that limit immune cell penetration and form an immune-excluded tumor phenotype. ECM proteins such as collagen I, collagen III, and elastin suppress NK cell cytotoxicity and shift their function toward cytokine production, thereby limiting their ability to eliminate MHC-I–deficient tumor cells in solid tissues. Blocking ECM deposition restores NK-mediated tumor killing [83]. In multiple solid tumors, including pancreatic ductal adenocarcinoma, this results in increased interstitial pressure and tissue stiffness, hindering both cytotoxic lymphocytes and NK cells from reaching malignant cells( [84, 85]). Additionally, stromal remodeling generates metabolic gradients and mechanotransduction signals that support tumor cell survival and may influence ferroptosis susceptibility [86], though direct connections between ECM rigidity and ferroptosis in NK cells remain to be validated.

Therapeutic implications and future perspectives

As research elucidates the intricate interplay between NK cells and ferroptosis within the tumor microenvironment, multiple therapeutic strategies have emerged to harness this crosstalk for improved cancer treatment. These approaches range from pharmacological induction of ferroptosis, cellular engineering of NK cells, modulation of immunosuppressive metabolic and cellular components in the tumor microenvironment, to combination regimens incorporating immune checkpoint blockade. Table 1 summarizes the current landscape of these therapeutic modalities, highlighting their mechanisms, evidence from preclinical and clinical studies, and associated challenges. The following sections discuss these strategies in detail, exploring their potential and limitations in clinical translation.

Table 1.

Comprehensive overview of therapeutic strategies targeting NK-ferroptosis crosstalk in cancer

Strategy category	Agents/Approaches	Mechanisms of action	Representative tumor models	Key preclinical findings	Clinical development status	Main challenges and considerations	References
Ferroptosis inducers	Erastin, RSL3, GPX4 inhibitors	Inhibit system Xc⁻ or GPX4 → increase lipid peroxidation	Melanoma, pancreatic cancer, glioblastoma	Synergize with NK cell killing, enhance ferroptotic death	Phase I/II trials ongoing	Dose toxicity, tumor selectivity, off-target effects	[49, 87]
Engineered NK cells	CAR-NK (IFN-γ secreting, ROS-enhanced)	Boost NK cytotoxicity and local oxidative stress	Lung, ovarian, colorectal cancers	Improved infiltration and ferroptosis sensitization	Preclinical stage	Persistence, exhaustion, safety, immunogenicity	[88]
TME metabolic modulators	A2A receptor antagonists, IDO inhibitors, MCT blockers	Relieve immunosuppression, restore NK function, disrupt tumor metabolism	Colorectal, lung, pancreatic cancers	Restore NK activity, reduce ferroptosis resistance	Early-phase clinical trials	Patient stratification, resistance mechanisms	[89]
Immunosuppressive cell targeting	CSF1R inhibitors, Treg depletion agents	Reprogram TAMs/MDSCs/Tregs, enhance NK activity	Melanoma, colon carcinoma	Increase NK infiltration, decrease SLC7A11 and GPX4	Preclinical and some clinical	Off-target immune effects, combination optimization	[90]
Hypoxia-targeting therapies	HIF inhibitors, CD73 blockade	Normalize oxygen levels, reduce adenosine-mediated suppression	Lung adenocarcinoma, glioblastoma	Restore NK receptor expression, sensitize tumors	Early clinical trials	Hypoxia heterogeneity, systemic effects	[91]
ECM remodeling agents	Hyaluronidase, collagenase, YAP inhibitors	Decrease ECM stiffness, improve NK infiltration	Pancreatic, breast cancers	Enhance NK motility, reduce ferroptosis resistance	Preclinical	Delivery efficiency, matrix complexity	[92]
Combination with checkpoint blockade	Anti-PD-1, anti-TIGIT	Reverse NK exhaustion, potentiate ferroptosis-induced immunity	Various solid tumors	Synergistic antitumor effects, improved survival	Several clinical trials ongoing	Immune-related adverse events, patient selection	[88]

Ferroptosis inducers synergize with NK-based immunotherapy

Recent preclinical studies have demonstrated that ferroptosis inducers markedly enhance the efficacy of NK cell–mediated tumor killing. Small molecules such as erastin and RSL3, which inhibit system Xc⁻ and GPX4 respectively, sensitize tumor cells by disrupting their antioxidant defenses and promoting lethal lipid peroxidation. When combined with activated NK cells or adoptive NK cell transfer, these agents amplify tumor cell susceptibility to immune cytotoxicity. For instance, in prostate cancer models, ferumoxytol-induced ferroptosis enhanced NK cell cytotoxicity and IFN-γ production, leading to greater tumor regression compared to either treatment alone [49]. In addition, the hybrid nanovesicles (hNRVs) combining NK cell-derived exosomes and RSL3-loaded liposomes actively accumulated in tumors, releasing FASL, IFN-γ, and RSL3 into the tumor microenvironment [93]. FASL induced tumor cell lysis, RSL3 inhibited GPX4 expression, promoting ferroptosis, while IFN-γ and TNF-α stimulated dendritic cell maturation, enhancing the immune response and indirectly promoting ferroptosis [93]. These synergistic effects highlight the potential of integrating ferroptosis inducers into NK-based immunotherapies to overcome tumor immune evasion and ferroptosis resistance. However, dose optimization and timing are critical to balance tumor cell killing with minimizing off-target toxicity.

Engineered NK cells to exploit ferroptotic vulnerabilities

Genetic engineering of NK cells, especially CAR-NK cells, offers promising avenues to enhance antitumor efficacy beyond natural cytotoxicity( [94, 95]). Currently, there is a lack of direct experimental evidence linking CAR-NK cell therapies with ferroptosis induction in tumor cells. While CAR-NK cells have demonstrated potent cytotoxicity against various cancers, and ferroptosis has emerged as a critical form of regulated cell death influencing tumor sensitivity, the integration of these two fields remains unexplored. Future research is warranted to investigate whether genetically engineered CAR-NK cells can be optimized to modulate ferroptosis pathways—either by enhancing ferroptotic tumor cell death or by resisting ferroptosis themselves within the tumor microenvironment. Such studies could open new avenues for synergistic cancer immunotherapies that combine precise immune targeting with metabolic vulnerabilities.

Challenges and outlook for clinical translation

Although the preclinical evidence supporting the combination of NK cell-based therapies with ferroptosis modulation is compelling, several critical challenges must be addressed before these approaches can be successfully translated into clinical practice.

Tumor microenvironment heterogeneity and patient stratification

One of the foremost obstacles is the profound heterogeneity of the tumor microenvironment across different cancer types and even among patients with the same tumor( [96, 97]). The TME consists of complex and dynamic interactions involving metabolic conditions, immunosuppressive factors (e.g., regulatory T cells, myeloid-derived suppressor cells), and stromal components (e.g., cancer-associated fibroblasts). These factors intricately influence both NK cell function and the sensitivity of tumor cells to ferroptosis. For example, elevated levels of lipid peroxidation substrates or iron availability may vary widely, affecting ferroptosis induction efficiency [98]. Therefore, a deep mechanistic understanding and precise profiling of the TME are necessary. Developing robust biomarkers that reflect TME metabolic and immunological status will enable better patient stratification, ensuring that only those patients whose tumors are most susceptible to NK-ferroptosis combinational strategies are selected for treatment.

Immunogenicity of ferroptotic cell death

Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. Unlike apoptosis, ferroptosis can release DAMPs such as HMGB1 and oxidized phospholipids, which have dual roles in modulating immune responses. On one hand, these DAMPs can promote dendritic cell maturation and activate antitumor immunity; on the other hand, they may induce immune tolerance or suppress effector cell functions depending on context and timing. This ambivalent immunogenicity poses a challenge for clinical translation, as the net immune consequence of ferroptosis induction in tumors remains incompletely understood. Carefully designed clinical studies are needed to evaluate how ferroptosis influences the tumor-immune landscape, including potential impacts on NK cell recruitment, activation, and exhaustion.

NK cell exhaustion and persistence

A major limitation of current NK cell therapies is the phenomenon of NK cell exhaustion, characterized by impaired cytotoxic function and cytokine production after chronic exposure to tumor antigens and suppressive signals [99–101]. Moreover, NK cells often exhibit limited in vivo persistence post-infusion, curtailing their therapeutic durability( [102, 103]). While ferroptosis modulation has shown potential to enhance antitumor immunity, it alone may not fully overcome the challenges of NK cell exhaustion and limited persistence within the tumor microenvironment. Immune checkpoint blockade therapies, such as PD-1/PD-L1, NKG2A inhibitors, have demonstrated efficacy in reinvigorating exhausted immune cells, including NK cells( [104, 105]). Although direct experimental evidence combining ferroptosis inducers with checkpoint inhibitors to restore NK cell function is currently lacking, mechanistic insights from separate studies suggest that such combination strategies could synergistically enhance NK cell–mediated antitumor responses. This hypothesis warrants further investigation through rigorous preclinical and clinical studies to optimize therapeutic regimens and fully realize the potential of NK-ferroptosis–based cancer immunotherapies. Additionally, metabolic support strategies—such as cytokine supplementation (e.g., IL-15) or modulation of tumor metabolic pathways—could further enhance NK cell fitness and resistance to the hostile TME( [106, 107]).

Current clinical landscape and future directions

Encouragingly, preclinical studies have demonstrated the potential of ferroptosis inducers combined with NK cell-based therapies or immune checkpoint blockade in various solid tumor models. Although early-phase clinical trials specifically evaluating such combinations remain limited or have not yet been widely reported, ongoing research is beginning to explore these strategies. However, these approaches face significant challenges including optimizing dosing regimens, scheduling, and patient selection criteria. The development of robust and dynamic biomarkers to monitor ferroptosis induction, NK cell activation, and overall immune responses will be critical to guide clinical decision-making. Furthermore, thorough safety evaluations are essential to assess potential adverse effects associated with ferroptosis modulation, such as unintended lipid peroxidation damage to normal tissues.

In conclusion, overcoming the multifaceted challenges of TME heterogeneity, immune modulation, and NK cell functionality will be crucial for the successful clinical translation of NK-ferroptosis combinational therapies. Interdisciplinary research integrating tumor biology, immunology, and clinical oncology is essential. With continued innovation in biomarker discovery, combination regimen optimization, and mechanistic insights, NK-ferroptosis–based immunotherapy holds great promise to become a powerful addition to the cancer treatment arsenal.

Abbreviations

4-HNE

4-hydroxynonenal

8-OHG

8-hydroxydeoxyguanosine

ACSL4

Acyl-CoA Synthetase Long Chain Family Member 4

CAFs

Cancer-associated fibroblasts

CAR-NK

Chimeric antigen receptor-engineered natural killer

DAMPs

Damage-associated molecular patterns

ECM

Extracellular matrix

ER

Endoplasmic Reticulum

GLS

Glutaminase

GPX4

Glutathione peroxidase 4

GSH

Glutathione

HIF-1α

Hypoxia-inducible factor 1-alpha

HMGB1

High-mobility group box 1

hNRVs

Hybrid nanovesicles

IFNγ

Interferon gamma

iNKT

Invariant natural killer T cells

MOMP

Mitochondrial outer membrane permeabilization

MUFA

Monounsaturated Fatty Acid

NK cell

Natural Killer cell

oxPEs

Oxidized phosphatidylethanolamines

PBMCs

Peripheral blood mononuclear cells

PSMA

Prostate-specific membrane antigen

PUFA

Polyunsaturated Fatty Acid

PUFA-CoA

Polyunsaturated Fatty Acyl-CoA

PUFA-PL

PUFA-containing Phospholipids

SCD1

Stearoyl-CoA Desaturase 1

scRNA-seq

Single-cell RNA sequencing

SFA

Saturated Fatty Acid

SLC7A11

Solute Carrier Family 7 Member 11

TNFα

Tumor Necrosis Factor alpha

TME

The tumor microenvironment

TNF-α

Tumor necrosis factor-alpha

Authors’ contributions

X.Y conceived the idea, organized the article and critically modified the manuscript. J.S wrote the manuscript. S.P, N.W and X.M sourced the literature and edited the article. All authors read and approved the manuscript.

Funding

This research was funded by the Science and Technology Department of Jilin Province (YDZJ202301ZYTS089, to Xige Yang) and the Jilin Provincial Education Department Project (JJKH20241340KJ, to Shu Pan).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.