The diverse origins and functional variability of TAMs (Figure 2) pose considerable difficulties for their ontological classification (26). Historically, tumor-associated macrophages were defined as immune cells capable of phagocytosing cancer cells, resulting in lethal consequences, and were initially categorized as anti-tumorigenic entities (27). Recent studies, however, have demonstrated their primary tumor-promoting role (28). The notable plasticity and diversity of tumor-associated macrophages, due to intra-tumoral heterogeneity and inter-patient variability, complicates the identification of consensus biomarkers or ontological systems that can differentiate between tumor-promoting and anti-tumor TAM phenotypes. TAM features can be dynamically changed during tumor growth or in response to therapeutic interventions, including targeted therapies and conventional radiotherapy or chemotherapy regimens (29). The biological complexities have made TAM definitions and ontologies dependent on the dimensionality of the analytical methods available for their development. Initially, flow cytometry enabled the preliminary classification of tumor-associated macrophage subsets (30). However, multidimensional techniques have refined or complicated these classifications, including single-cell omics technologies (31). Various TAM classification schemes exist, each relying on health versus illness states, particular clinical situations, tissue type specificity, or functional activity patterns.

Macrophages exhibit remarkable heterogeneity and adaptability, rapidly responding to environmental cues by polarizing into functionally distinct phenotypes. Under stimulation by lipopolysaccharide (LPS) and interferon-γ (IFN-γ), macrophages adopt the M1 phenotype (32). These classically activated M1 macrophages produce pro-inflammatory mediators, including IFN-γ, tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) (33). Metabolically, M1 macrophages exhibit enhanced glycolytic activity, elevated ferritin expression, reduced membrane iron transporter levels, increased glutathione content, upregulated cyclooxygenase-2 (COX2) with concurrent downregulation of cyclooxygenase-1 (COX1), and heightened iNOS2 activity alongside diminished arginase-1 (Arg1) function (34). Conversely, cytokines such as IL-4, IL-13, and macrophage colony-stimulating factor (M-CSF) drive polarization toward the M2 phenotype, which secretes anti-inflammatory factors including IL-4, IL-10, and IL-13 (35). M2 macrophages characteristically express elevated levels of mannose receptor (CD206), resistin-like molecule α, Arg1, and chitinase. The production of IL-10 and IL-1 receptor antagonists generates various anti-inflammatory cytokines, which are essential for tissue repair and remodeling following pathogen-induced damage (36, 37).

Tumor-associated macrophages (TAMs) represent macrophages recruited and reprogrammed by the tumor microenvironment (TME), exhibiting distinct functional differences from conventional immune macrophages. M2-polarized TAMs collaborate with angiogenic factors, including epidermal growth factor (EGF) and placental-derived growth factor, within the TME. Their secretion of matrix metalloproteinases (MMPs), serine proteases, and cathepsins disrupts the endothelial basement membranes, degrades extracellular matrix components, including collagen, and facilitates the migration of tumor and stromal cells, ultimately promoting tumor angiogenesis and metastasis (41). The tyrosine-protein kinase receptor 2 (Tie2) expressed by specific TAM subsets interacts with various angiopoietins to accelerate tumor dissemination. Therapeutic targeting of Tie2 significantly reduces TAM presence in tumors, effectively controlling cancer cell proliferation and spread (8), thereby inhibiting tumor growth. TAMs regulate tumor cell proliferation through numerous growth factors and receptors, including EGF, platelet-derived growth factor, transforming growth factor-β1 (TGF-β1), hepatocyte growth factor, epidermal growth factor receptor (EGFR) ligands, and basic fibroblast growth factor (42). Additionally, TAMs indirectly modulate tumor growth through complex signaling networks affecting immune and angiogenic cells within the TME. These regulatory mechanisms encompass gene expression, protein modification, and intercellular communication, with TAMs precisely orchestrating tumor cell growth, development, invasion, and metastasis through diverse signaling pathways (43, 44).

Dixon defined ferroptosis as a unique type of controlled cell death in 2012, based on its iron-dependent mechanism and fundamental deviations from apoptotic pathways (45, 46). Lipid hydroperoxides accumulating gradually inside cell membranes define this process. Among other illnesses of the cardiovascular system, neurological ailments, hepatotoxicity, and renal damage, a growing body of evidence has connected ferroptotic pathways to the etiology of numerous clinical conditions (1–4). Ferroptosis’s biochemical signature involves the oxidative degradation of phospholipid membranes through both enzyme-catalyzed and spontaneous chemical processes (47, 48). Key molecular features of ferroptotic cells include abnormal iron accumulation and dysfunction of glutathione peroxidase 4 (GPX4), thereby highlighting the complex interplay of this process with cellular pathways regulating iron homeostasis, lipid metabolism, and amino acid processing (Figure 3).

Ferroptosis involves aberrant iron metabolism, resulting in lipid peroxidation and the degradation of cellular membranes. Typically, extracellular Fe³⁺ is sequestered by transferrin, then reduced to Fe²⁺ within the cell, with any surplus exported by SLC40A1 (49). Excess Fe²⁺ is usually sequestered in ferritin; when this process is compromised, Fe²⁺ activates lipid peroxidases, producing reactive oxygen species (50), which oxidize membrane polyunsaturated fatty acids (PUFAs) to PUFA-OOHs, resulting in irreversible membrane damage and cellular apoptosis (Figure 4). Intracellular and extracellular mechanisms govern Ferroptosis inside the tumor immune microenvironment (TIME). The primary intracellular regulator is the Xc^-/GSH/GPX4 axis. System Xc^-, a heterodimer composed of xCT (SLC7A11) and 4F2 (SLC3A2) (51), facilitates the import of cystine and the export of glutamate, hence supplying precursors for glutathione production. GSH mitigates reactive oxygen species and lipid hydroperoxides through the action of GPX4. Ferroptosis inducers such as erastin obstruct this route by inhibiting SLC7A11, while concurrently activating mitochondrial VDACs, upregulating ACSL4, and indirectly stimulating p53. Recently discovered GSH-independent compounds, such as FSP1, also modulate tumor ferroptosis (52).

CD8⁺ T cells predominantly trigger ferroptosis in malignancies through extracellular mechanisms. They demonstrated that T cell-derived IFN-γ activates the JAK/STAT1 pathway, resulting in the formation of STAT1 homodimers that inhibit SLC7A11 transcription (53, 54). IFN-γ also elevates mitochondrial reactive oxygen species, presumably via the STAT1/NF-κB/NOS2 pathway. Furthermore, IFN-γ activates ACSL4, enabling the integration of arachidonic acid into phospholipids and thereby enhancing oxidative susceptibility (55, 56). Although IFN-γ augments the anti-tumor efficacy of CD8⁺ T cells, the tumor immune microenvironment (TIME) considerably affects this mechanism, possibly restricting ferroptosis in immunologically inert malignancies (57, 58). Identifying essential TIME regulators is vital for advancing effective ferroptosis-based cancer treatments.

Iron is a critical driver of lipid peroxidation and subsequent ferroptosis within cellular environments (60, 61). Research demonstrates that various iron metabolism-related genes regulate ferroptosis processes, including transferrin, nitrogen fixation system 1 (NFS1), iron-responsive element-binding protein 2 (IREB2), nuclear receptor co-activator 4 (NCOA4), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4)—each representing key genetic determinants of ferroptosis susceptibility (62, 63).

Diminished activity of the cystine/glutamate antiporter (system Xc-) serves as the initial trigger for ferroptosis (64, 65). When the system Xc-function becomes compromised, cellular cystine uptake decreases, leading to reduced glutathione (GSH) synthesis and consequent elevation of lipid ROS levels, ultimately culminating in ferroptosis cell death (66).

Ferroptosis substrates primarily include polyunsaturated fatty acids (PUFAs, characterized by their abundance of double bonds), free polyunsaturated fatty acids such as oxidized arachidonic acid, and adrenal hormones. These fatty acids induce ferroptosis through esterification and incorporation into cellular membrane phospholipids (67). Intracellularly, ROS facilitate the integration of oxidized free polyunsaturated fatty acid products into biological membranes, including plasma and mitochondrial membranes, as shown in Table 1. This integration compromises membrane function, reducing biological membrane fluidity and leading to impaired cellular energy production, disruption of biological membrane integrity, and restricted material exchange, collectively disrupting normal cellular physiology.

Macrophages provide essential material requisites for ferroptosis through their ability to uptake and store iron ions. When macrophages encounter specific stimuli, they phagocytose ferroptotic pancreatic cancer cells harboring KRAS-G12D mutations. This interaction promotes M2 macrophage polarization, enhancing pro-tumorigenic phenotypes (68). Infection, injury, and inflammation stimulate macrophage iron uptake and storage, thereby facilitating the induction of ferroptosis. M1-polarized macrophages secrete ferroptosis-inducing factors that act on neighboring cells and efficiently eliminate post-ferroptotic necrotic cells through phagocytosis. During this process, macrophages perform crucial clearance functions that maintain tissue and organ homeostasis (69). Conversely, M2-polarized macrophages secrete cytokines such as IL-10 and TGF-β, which activate anti-ferroptotic signaling cascades within tumor cells. These cascades regulate antioxidant enzymes, such as GPX4, inhibit lipid peroxidation reactions, and suppress tumor cell ferroptosis.

Tumor-associated macrophages (TAMs) and ferroptotic cancer cells engage in a highly integrated, bidirectional metabolic dialogue that shapes immune outcomes and determines tumor (70). This crosstalk is governed by iron flux, lipid remodeling, amino-acid metabolism, mitochondrial redox balance, and cytokine-driven signaling loops. M1-like macrophages amplify ferroptotic pressure through ferritinophagy-mediated release of labile Fe²⁺, increased transferrin receptor (TfR1) expression, and restricted ferroportin activity, thereby enriching the tumor microenvironment (TME) with redox-active iron (71). Elevated nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ) further inhibit SLC7A11 and destabilize GPX4 activity in cancer cells. These macrophage-derived metabolic signals synergistically increase lipid peroxidation through the ACSL4-dependent synthesis of PUFA-phospholipids, pushing cancer cells beyond their antioxidant capacity and into a state of ferroptosis. By contrast, M2-like TAMs create a ferroptosis-resistant niche through high ferroportin expression, heme degradation pathways (HMOX1), the generation of antioxidant glutathione, and the secretion of IL-10 and TGF-β (72). These cues reinforce GPX4 activity, suppress lipid peroxidation, and modulate NADPH-dependent regeneration pathways, collectively shielding tumor cells from ferroptotic damage. Lipid-associated TAM subsets additionally supply oxidized cholesterol derivatives and anti-inflammatory lipid mediators that reinforce immune tolerance and inhibit ferroptosis execution.

Ferroptotic cancer cells reciprocally influence macrophage states by releasing DAMPs (HMGB1), oxidized phosphatidylethanolamines (SAPE-OOH), iron-loaded vesicles, and lipid peroxidation products that serve as signals to recruit, polarize, or reprogram macrophages (73). Early ferroptotic intermediates can promote M1 activation, whereas chronic ferroptotic stress and lipid peroxides tend to skew macrophages toward immunosuppressive phenotypes, as shown in Figure 5. These reciprocal loops define a dynamic immunometabolic axis that determines whether ferroptosis amplifies anti-tumor immunity or reinforces tumor tolerance.

Tumor-associated macrophages (TAMs) orchestrate ferroptotic sensitivity in cancer cells through a set of tightly interlinked metabolic and immunological interactions (74). M2-like TAMs, which dominate many solid tumors, create a ferroptosis-resistant niche by exporting iron through ferroportin, supplying cysteine precursors that support glutathione synthesis, and releasing IL-10, TGF-β, and lipid mediators that dampen oxidative stress. These signals collectively stabilize GPX4 activity and limit lipid-peroxide accumulation, thereby shielding tumor cells from ferroptotic death. In contrast, M1-like TAMs impose a ferroptosis-promoting environment through ferritin degradation (ferritinophagy), release of labile iron, production of nitric oxide and ROS, and secretion of pro-inflammatory cytokines that suppress SLC7A11 function and perturb GSH biosynthesis (75). Through ACSL4 induction and provision of oxidizable PUFA substrates, M1 TAMs directly enhance the lipid-peroxidation machinery necessary for ferroptosis execution.

Bidirectional signaling further reinforces this crosstalk: tumor-cell–derived lactate, HMGB1, prostaglandins, and oxidized lipids polarize macrophages toward either ferroptosis-promoting (M1-like) or ferroptosis-restraining (M2-like) states. Ferroptotic cancer cells also release danger-associated lipids and iron intermediates that recruit and activate macrophages, creating positive or negative regulatory loops (76). This integrated metabolic–immune dialogue determines whether ferroptosis proceeds or is suppressed within the tumor microenvironment, representing a central axis of TAM-mediated control over tumor progression.

During early tumorigenesis, M1-type tumor-associated macrophages (TAMs) facilitate cellular iron uptake via transferrin receptor 1 (TfR1/CD71), while ferritin (FT) restricts iron efflux, resulting in iron sequestration. Pro-inflammatory cytokines, including IL-6, IL-1, and TNF-α, promote M1-type TAM formation, inhibit iron release into the tumor immune microenvironment (TIME), and exert anti-tumor effects (77). In circulation, ferric ions (Fe³⁺) bind to FT for transport throughout the body. Upon reaching target tissues, iron is absorbed by cells through the transferrin receptor 1 (TfR1) receptor. Intracellularly, iron undergoes reduction to its ferrous form (Fe²⁺) by the reductase six-transmembrane epithelial antigen of prostate 3 (STEAP3) before entering the cytoplasm through divalent metal transporter 1 (DMT1). TfR1 recycles to the cell surface during this process for continued iron transport. Regulating TAM iron metabolism within the TIME, specifically by promoting iron uptake and storage in M2-type macrophages while inhibiting iron release, allows iron accumulation in TAMs to enhance ROS production, increase p300/CBP acetyltransferase activity, and promote p53 acetylation. These changes drive conversion to the pro-inflammatory M1 phenotype, which exhibits anti-tumor properties (78). In contrast, M2-type macrophages demonstrate enhanced iron efflux capacity through higher ferroportin (FPN) expression and lower FT levels, inducing elevated CD91 or CD163 expression (79). CD163, a cell surface protein with high binding affinity for specific substrates, is a distinctive M2-type TAM marker. These macrophages play significant roles in the tumor microenvironment, typically promoting tumor growth and dissemination. CD163 facilitates efficient hemoglobin phagocytosis by these macrophages, enabling iron acquisition. As iron is essential for cellular proliferation, CD163 indirectly supports tumor cell growth (80).

M2-type TAMs enhance intracellular heme accumulation by phagocytosing senescent erythrocytes. Following heme internalization, heme oxygenase-1 (HMOX-1) degrades heme to produce bilirubin, carbon monoxide, and ferrous ions, which inhibit the interactions of iron-binding proteins with iron response elements in FPN mRNA, thereby upregulating FPN expression and promoting tumor growth (81). Consequently, M2-type TAMs within the TIME facilitate iron transport to the extracellular environment, suppress recruitment and cytotoxic function of tumoricidal immune cells, stimulate angiogenesis, and enhance tumor cell proliferation, invasion, and metastasis. Leveraging the relationship between macrophage polarization phenotypes and iron metabolism, therapeutic targeting of TAMs within the TME represents a promising anti-tumor strategy (2). Researcher demonstrates that tumor-delivered iron nanoparticles, when internalized by TAMs, promote their conversion to tumor-suppressive M1-type macrophages (82). The FDA-approved iron supplement ferumoxytol (an iron oxide nanoparticle) has been shown to inhibit subcutaneous adenocarcinoma development in mice by promoting TAM polarization toward the M1 phenotype and preventing hepatic tumor metastasis. Further investigation is needed to determine the optimal M1/M2 macrophage balance in relation to iron metabolism within the tumor microenvironment.

Macrophages exhibit remarkable plasticity, changing their phenotype and functional spectrum in response to the microenvironment, thereby demonstrating the existence of heterogeneous subpopulations. Macrophage polarization has a critical influence on tumor development and the regulation of ferroptosis. Traditionally, activated macrophages are classified into two main types: proinflammatory M1 macrophages and anti-inflammatory M2 macrophages. However, this binary classification has faced recent criticism (83). M1 macrophages, induced by Toll-like receptor ligands (e.g., LPS) or Th1 cytokines such as TNF-α, IFN-γ, and colony-stimulating factor 2 (CSF2), are characterized by surface expression of TLR2, TLR4, CD80, and CD86 (84). With high antigen-presenting capacity, they secrete reactive oxygen species (ROS) and proinflammatory cytokines, including IL-1, IL-6, IL-12, IL-18, IL-23, and TNF-α, which modulate Th1-mediated antigen-specific inflammatory responses (85, 86). M1 macrophages enhance inducible nitric oxide synthase (NOS2 or iNOS) expression, thereby promoting NO production from L-arginine (79). Their infiltration is considered a favorable prognostic factor in tumors (87, 88). These M1-derived inflammatory mediators have a significant impact on ferroptosis pathways. Notably, macrophage-derived TNF-α plays a role in modulating ferroptosis susceptibility in cellular populations. Mechanistically, TNF-α induces SLC7A11 and the glutamate-cysteine ligase modifier subunit by activating nuclear factor-κB (NF-κB), which upregulates the regulatory subunit of glutamate-cysteine ligase catalytic (GCLC) and glutamate-cysteine ligase catalytic, ultimately enhancing cellular GSH biosynthesis and protecting against lipid peroxidation-induced stress, thereby increasing ferroptosis resistance (89).

In contrast, M2 macrophages, induced by IL-4, IL-13, IL-10, or glucocorticoids, produce anti-inflammatory cytokines, primarily TGF-β and IL-10 (90). By creating an immunosuppressive environment, M2 macrophages are frequently classified as tumor-associated macrophages (91). Their secreted TGF-β and IL-10 inhibit cytotoxic T lymphocytes and CD4+ T cells; however, some evidence suggests that TAMs include both M1 and M2 phenotypes (92). During tumor progression, macrophage-derived TGF-β1 can inhibit transcription through SMAD signaling, thereby promoting ferroptosis (85) and thus representing a complex interplay between immunosuppressive cytokines and ferroptotic mechanisms. M2 macrophages exhibit angiogenic and proinvasive properties, producing growth factors, chemokines, and MMPs that stimulate tumor growth, invasion, and metastasis (93), particularly facilitating tumor cell extravasation and growth in secondary sites. Different macrophage subpopulations regulate each process, and experimental studies demonstrating tumor inhibition through macrophage depletion confirm the critical role of tumor-immune cell interactions in cancer progression. Beyond the traditional M1-M2 paradigm, current transcriptomic analyses reveal greater TAM diversity with seven main subtypes: interferon-primed TAMs (IFN-TAMs), immune regulatory TAMs (Reg-TAMs), inflammatory cytokine-enriched TAMs (Inflam-TAMs), lipid-associated TAMs (LA-TAMs), proangiogenic TAMs (Angio-TAMs), RTM-like TAMs (RTM-TAMs), and proliferating TAMs (Prolif-TAMs) (Figure 6) (94).

This advanced classification provides a framework for understanding the diverse roles of macrophages in regulating ferroptotic. The phagocytic capacity of macrophages toward ferroptotic tumor cells demonstrates anti-tumor activity, with various immune-stimulatory signals released by ferroptotic tumor cells enhancing phagocytic efficiency (95). This ferroptosis-phagocytosis axis represents a promising anti-cancer therapeutic approach, potentially exploitable through the targeted induction of ferroptosis in tumor environments heavily infiltrated by specific macrophage subtypes.

Ferroptosis occurs in various disease states, with macrophages responsible for ferroptotic cell clearance. Ferroptotic cells activate macrophage functions and recruitment through damage-associated molecular patterns (DAMPs), which are endogenous danger signals that recruit and activate macrophages, thereby initiating immune defense mechanisms. Studies demonstrate that during ferroptosis, ferroptotic cells release the autophagy-dependent DAMP high-mobility group box 1 (HMGB1). HMGB1-mediated macrophage inflammation requires the receptor for advanced glycation end products (101, 102). In ferroptosis response, macrophage Toll-like receptor 2 (TLR2) initially interacts with oxidized phospholipid peroxides and 1-stearoyl-2-15-hPEtE-sn-glycero-3-phosphatidyl-ethanolamine (SAPE-OOH) on ferroptosis cell surfaces, enhancing macrophage phagocytosis efficiency. Notably, the depletion of anti-HMGB1 neutralizing antibody or arginine catabolism enzyme (AGRE) mitigates macrophage inflammatory responses, suggesting that restricting HMGB1 expression may be a potential approach for managing macrophage inflammation (103, 104).

Beyond HMGB1, ferroptosis cells trigger inflammatory responses and promote macrophage recruitment by activating molecular pathways that induce inflammation. They induce the expression of inflammation-related genes, including CCL2 and CCL7, which enhance macrophage recruitment and chemotaxis (105).

Iron metabolism is quite crucial for macrophage phenotypic differentiation. Essential micronutrient iron coordinates several cellular functions, including proliferation, metabolic activity, and cellular differentiation. The physiological iron supply mostly depends on macrophage-mediated recycling of erythrocyte iron over complex regulatory routes. Especially in embryonic and differentiation settings, iron availability significantly affects the determination of macrophage destiny and functional programming. Macrophages first store iron intracellularly, mostly in ferritin (Ft) complexes. Iron-regulating gene expression profiles exhibit distinct trends corresponding to the stages of macrophage polarization. With concurrent downregulation of ferroportin (FPN) and iron-regulating proteins (IRP1/2), M1-polarized macrophages show increased hepcidin (Hamp) and ferritin heavy/light chains (FTH/FTL) relative to their M2 counterparts (96).

Usually, iron abundance favors M1 polarization. Excessive iron loading increases the expression of M1-associated inflammatory mediators, including IL-6, TNF-α, and IL-1β, while suppressing M2 markers such as transglutaminase 2 (TGM2), so efficiently guiding polarization toward the pro-inflammatory M1 phenotype (97). Apart from inflammatory cytokine production, iron excess has been shown to exacerbate atherosclerosis development by enhancing glycolytic metabolism, thereby supporting the M1 phenotype (98). Furthermore, iron overload promotes M1 polarization using enhanced p53 acetylation and reactive oxygen species production (99). However, the link between iron loading and macrophage polarization exhibits context dependence; studies from 2020 demonstrate that chronic iron excess conditions induce an M2-like phenotype in THP-1 monocyte-derived macrophages, concurrently downregulating M1 markers (100).

Many clinical diseases cause ferroptotic cell death, and macrophages are the primary effectors in ferroptotic cell clearance. As previously mentioned, the macrophage’s phagocytic ability is a cornerstone of immunological surveillance. Ferroptotic cells actively influence macrophage functional responses and recruitment dynamics (Figure 7). As endogenous danger signals, damage-associated molecular pattern molecules (DAMPs) enable macrophage recruitment and activation, alerting the immune system. During ferroptosis, cells release the DAMP high-mobility group box 1 (HMGB1) by autophagy-dependent processes. The sophisticated glycosylation end-product-specific receptor controls macrophage inflammatory responses by HMGB1 (101).

Present on ferroptotic cell surfaces, macrophage toll-like receptor 2 (TLR2) initially interacts with oxidized phospholipids, specifically 1-stearoyl-2-15-HpETE-sn-glycero-3-phosphatidyl-ethanolamine (SAPE-OOH), therefore improving phagocytic effectiveness. Moreover, neutralizing HMGB1 with specific antibodies or depleting HMGB1 reduces inflammatory activation in macrophages, implying that HMGB1 inhibition may be a possible therapeutic strategy for controlling macrophage-mediated inflammation (103). Beyond HMGB1 signaling, ferroptotic cells activate other molecular inflammatory pathways, triggering inflammatory reactions and the recruitment of macrophages. With a special focus on chemokines CCL2 and CCL7, which facilitate macrophage chemotaxis and recruitment, ferroptosis enhances the expression of many inflammation-associated genes (102).

The metabolic diversity of TAM subsets provides multiple therapeutic entry points for modulating ferroptosis in cancer cells. M1-like macrophages, characterized by elevated glycolysis, disrupted TCA cycle intermediates, enhanced ferritinophagy, and high ROS/NO production, naturally promote ferroptotic pressure. Therapeutically, these cells can be further potentiated using agents that intensify iron release (e.g., NCOA4 activators), enhance ACSL4-mediated PUFA incorporation, or inhibit GPX4-stabilizing pathways (106). Targeting metabolic checkpoints such as PKM2 or succinate oxidation can increase the availability of redox-active metabolites that accelerate lipid peroxidation in tumor cells. In contrast, M2-like macrophages, driven by oxidative phosphorylation, fatty-acid β-oxidation, and glutathione synthesis, constitute a ferroptosis-inhibitory niche. These cells can be reprogrammed metabolically using FAO inhibitors (etomoxir), glutathione-depleting drugs (buthionine sulfoximine), or ferroportin blockers to decrease iron efflux. Suppression of IL-10/STAT3 or TGF-β/SMAD-dependent antioxidant circuits enables the restoration of lipid peroxidation susceptibility in adjacent tumor cells (107). Additionally, M2-associated iron recycling pathways (HMOX1 upregulation, heme metabolism) can be targeted to shift intracellular iron pools toward pro-ferroptotic states. Lipid-associated TAMs (LA-TAMs) represent a third emerging subset with high expression of lipid uptake receptors, cholesterol efflux transporters, and PPAR-driven immunosuppressive programs (108). Therapeutic interventions aimed at modulating lipid availability, such as ACAT inhibitors, PPAR antagonists, or scavenger-receptor blockade, can reduce the supply of anti-ferroptotic lipid mediators and promote oxidative lipid stress within tumor cells.

Collectively, these strategies demonstrate that metabolically targeting TAM subsets is a powerful approach to controlling ferroptosis, suggesting multiple avenues for combination therapies that integrate ferroptosis inducers, immune checkpoint modulators, and metabolic inhibitors.

The maintenance of cellular homeostasis and the prevention of proliferative diseases fundamentally rely on the controlled process of cell death (115). Cancer cells undergo a variety of regulated cell death processes during development, such as necrosis and apoptosis. Utilizing specific CCD pathways is a powerful and long-lasting approach to treating cancer. Although some contemporary anti-cancer drugs focus on apoptotic signals (116), newer studies emphasize that generating Ferroptosis is a possible innovative anti-cancer strategy, thus creating new therapeutic possibilities (117). Ferroptosis induced by tiny chemical substances, nanomaterials, exosomes, and genetic technology has shown considerable anti-tumor efficacy (Figure 8).

Nanoparticles (NPs) exhibit outstanding efficacy in precise targeting through both active and passive mechanisms. Although nanoparticle drugs have been rapidly incorporated into cancer treatment, they have encountered obstacles, including immunogenicity and cytotoxicity (118). The complexity of tumors requires the combination of Ferroptosis with other treatments. An innovative approach that combines Ferroptosis with photothermal therapy (PTT) using SRF@MPDA-SPIO-NPs, SPIO promotes Ferroptosis, and SRF induces Ferroptosis (119). MPDA-NPs provide adaptive photothermal therapy through laser-induced heat generation. The PTT-ferroptosis combination shows considerable anti-tumor potential. The activation of autophagy can also accelerate ferritin apoptosis by promoting the degradation of ferritin. Nanocomposites MnO2@HMCu2-xS (HMCM) have been used in cancer treatment by photothermal therapy (PTT) and autophagy-enhanced ferroapoptosis. MnO2 induces ferroapoptosis in the tumor microenvironment (TME) by consuming GSH, while photothermal therapy (PTT) and HMCU2-XS-induced ferroapoptosis have a synergistic effect. Ferroptosis also generates reactive oxygen species (ROS) by releasing Mn2+, serving as a supplementary mechanism for Ferroptosis induced by lipid hydrogen peroxide (120). In cancer treatment, genetic technologies include gene knockout and gene transfection methods (121). The primary genetic targets for treating ferroptosis may include p53, Gpx4, ACSL4, and Nrf2.

Regulation. Although nanotechnology has enhanced cancer treatment, the use of nanomaterials in this technology may exhibit cytotoxicity (122). Exosomes (30–120 nm lipid bilayer vesicles) possess superior biocompatibility, low immunogenicity, and tumor-targeting ability, making them the best drug delivery carriers. Traditional hormone and EGFR-targeted therapies are usually ineffective for triple-negative breast cancer (TNBC). A method named rastin@FA-Exo can enhance exosome transport and folate receptor uptake in triple-negative breast cancer (TNBC) cells, thereby enabling targeted drug delivery. Conversely, exosomes may also confer resistance to ferroptosis in tumor cells (123). Ferritin is an iron storage protein that was detected in exosomes of anti-apoptosis cells treated with Gpx inhibitors. During the induction of ptosis, the level of protruding protein 2 was negatively correlated with cellular iron. Cells continuously overexpress the iron export mechanism by transporting ferritin and iron through MVBs/exosomes, thereby limiting the accumulation of iron within the cells and inhibiting ferroptosis. Inactivating this pathway, whether spontaneously or through intervention, triggers factors that induce ferroptosis, underscoring the importance of regulating ferroptosis in cancer treatment (124). Under the stimulation of ferroptosis, the expression of protruding protein-2 in breast cancer cells increases, which can enhance the production of MVB/exosomes containing ferritin and promote iron excretion (125). The ferritin cascade, mediated by MVB-exosomes and Protrusion protein-2, may represent a novel approach to suppressing cancer by inhibiting Ferroptosis.

Resistance to radiotherapy and chemotherapy can lead to treatment failure, making Ferroptosis a new target for traditional treatment (126). Sorafenib is the primary therapeutic agent for advanced hepatocellular carcinoma (HCC), which can induce cell apoptosis, inhibit cell growth, and trigger ferroptosis. Nrf2, MTIG, and Rb have been proven to alleviate sorafenib-induced Ferroptosis. Inhibiting these regulatory factors may increase resistance to sorafenib. SAS inhibits xCT and is used for the treatment of arthritis and inflammatory bowel disease, which can lead to ferroptosis, a potential cancer treatment method, as shown in Table 2. Inhibition of CISD2 in HNCC can increase mitochondrial Fe2+ and reactive oxygen species (ROS), thereby enhancing the sensitivity of malignant tumors to Ferroptosis induced by SAS (127). Artemisinin and its derivatives can induce Ferroptosis by increasing reactive oxygen species.