Introduction
Studies have demonstrated that abnormalities in lipid metabolism are closely associated with malignant tumors. Reprogramming of lipid metabolism is recognized as a hallmark of many cancers and plays a pivotal role in facilitating tumor metastasis and progression.1 Consequently, regulating lipid metabolism in tumors represents an effective approach to preventing and treating malignant tumors.2
Tumor cells do not exist in isolation, and the tumor microenvironment provides tumor cells with necessary nutrients, maintains an appropriate pH, and ensures sufficient oxygen, all of which are important for tumor cell proliferation, invasion, and migration while emphasizing the critical role of the tumor microenvironment in cancer progression and providing a new avenue for further research and clinical prevention in the future.3 Therefore, an in-depth exploration of the interactions between lipid metabolism and the tumor microenvironment is important for elucidating the complexity of cancer biology and laying the theoretical foundation for novel preventive and therapeutic strategies.3 Regardless of oxygen availability in the tumor microenvironment, tumor cells rely on glycolysis as their primary energy source, a phenomenon known as the Warburg effect.4 This process allows tumor cells to rapidly adapt to the tumor microenvironment, promoting their malignant characteristics. The rapid proliferation of tumor cells increases their demand for energy and nutrients, resulting in an acidic and hypoxic tumor microenvironment. This microenvironment not only induces normal cells to die but also allows tumor cells to evade immune surveillance, as well as affecting the function of immune cells and activating lipid metabolism in tumor cells.5
A deep understanding of the interactions between the tumor microenvironment and lipid metabolism of tumor cells and its impact on immune responses is important for a comprehensive understanding of the immune function of tumor cells, as well as therapeutic approaches for cancer patients.6 Existing studies have emphasized the critical role of lipid metabolism in regulating immune cell function.5 Further research on strategies to effectively regulate lipid metabolism and identify novel lipid metabolism markers is expected to enhance the function of immune cells on the one hand, provide potential targets for early cancer screening and prevention on the other hand, and improve the efficacy of immunotherapy.7
This review highlights recent advances in the interactions between lipid metabolism and the tumor microenvironment.8 It also describes the effects of key metabolic molecules, such as fatty acids and cholesterol, on the function of immune cells and explores their roles in tumor immune escape and therapy.5 By analyzing the results of related studies, we aim to provide a scientific foundation and theoretical framework for early cancer screening, risk prediction, preventive interventions, and the development of tumor immunotherapy.9
Lipid metabolism in tumor cells
Lipids play crucial roles in cell formation, including signal transduction, formation of membrane structures, and energy storage. These functions are important in maintaining cellular homeostasis and facilitating biological pathways. Typically, lipids are categorized into eight major groups: fatty acids, glycerol, glycolipids, sphingolipids, sterols, pregnenolone lipids, glycolipids, and polyphospholipids.10 They are based on chemical principles and reflect the hydrophobic and hydrophilic components of lipids.
Lipids are ubiquitous in nature and essential components of living organisms, playing an important role in cell structure, growth, development, metabolism, and energy balance. In addition to their involvement in membrane formation and signal transduction, lipids are important energy reservoirs. Typically, it is stored as triglycerides, providing an efficient and long-term energy source. Stored energy plays an important role in maintaining metabolism during fasting, physical exertion, or increased metabolic demands, highlighting the important role of lipids in maintaining cellular and organismal energy. Therefore, understanding the diversity of lipids and their functions is essential for advancing the study of metabolic mechanisms related to cancer.10
Fatty acids
Fatty acids play a key role in tumor cells, particularly during energy metabolism and biosynthesis. Relevant studies have shown that fatty acids are usually stored in lipid droplets as triglycerides and can be released through lipolysis. Tumor cells generally rely on the de novo synthesis of fatty acids to obtain their essential lipids,11 and this pathway is found in various cancers, including esophageal, gastric, and hepatocellular carcinomas.12 In addition, acyl-CoA synthetase appears to be upregulated in many cancers, a phenomenon that promotes fatty acid anabolism; furthermore, ATP citrate lyase catalyzes the conversion of free fatty acids to the fatty acid acyl-CoA, a key intermediate in fatty acid biosynthesis.13
Fatty acid oxidation also plays a pivotal role in tumor cell invasion and metastasis, and the expression of related enzymes is closely related to tumor energy metabolism.14 In addition, the ratio of saturated fatty acids to unsaturated fatty acids affects membrane fluidity and function, thus regulating cell signaling.15 Cell membranes are mainly composed of phospholipid bilayers, and differences in lipid composition can significantly affect the physical properties of the membrane.16 Saturated fatty acids typically have a straight-chain structure, which allows lipid molecules to be tightly packed to form a denser membrane structure, which reduces membrane fluidity. In contrast, unsaturated fatty acids usually contain one or more double bonds, resulting in bending the fatty acid chain, increasing membrane fluidity.13 This difference directly affects the flexibility, fluidity, and membrane protein activity of cell membranes.17 Specific mechanisms include altering the physical properties of membranes, promoting, or inhibiting the formation of lipid microregions, and modulating the effects of fatty acid metabolites on signaling pathways.18 In addition, membrane protein fluidity and aggregation are similarly regulated by changes in fatty acid ratios. The fluid fluidity of membranes contributes to the aggregation or dispersion of membrane proteins in the membrane, which affects their activity and interaction with other signaling molecules or proteins. For example, ligand binding of receptors and activation or inhibition of enzymes may be regulated by changes in lipid composition, which can affect the efficiency and specificity of signal transduction.18
Recent studies have shown that dysregulation of fatty acid metabolism is closely associated with several diseases, including obesity, diabetes, and cancer.19 In related cancer studies, altered metabolism of specific fatty acids can promote tumor cell proliferation and metastasis.17 For instance, saturated fatty acids may activate relevant pro-inflammatory signaling pathways, thus promoting tumor development, whereas unsaturated fatty acids may exhibit tumor-suppressive properties.13 Further investigation into the mechanisms of fatty acid metabolism could enhance our understanding of their roles in related diseases and may also provide the foundation for novel therapeutic strategies.16 In conclusion, fatty acid metabolism is crucial for a deeper comprehension of tumor biology and its progression.15
Cholesterol
As an essential component of lipid metabolism, cholesterol is commonly found in cell membranes. Elevated cholesterol levels in tumor cells are crucial for maintaining cellular function; thus, increased cholesterol synthesis is recognized as one of the hallmarks of malignant tumorigenesis.20 Generally, cholesterol is synthesized into low-density lipoproteins and very low-density lipoproteins in the liver and transported through the bloodstream. However, excessive free cholesterol in cells reduces cell membrane fluidity and interferes with cell signaling. To mitigate this issue, cholesterol acyltransferase (ACAT) converts cholesterol into cholesteryl esters (CE), a process that is particularly pronounced in cancers associated with elevated cholesterol levels.21 While this process serves as a mechanism for cholesterol storage, it leads to an accumulation of pathologic lipids associated with cancers. Overactivation of the ACAT pathway exacerbates cholesteryl esterification, promotes the formation of lipid droplets, and potentially facilitates further growth of cancer cells. Therefore, targeting ACAT expression or activity in cancer may offer a novel therapeutic approach to modulate cholesterol metabolism, thereby balancing cholesterol stores and preventing the excessive accumulation of its harmful components.22
It has been shown that the transcription factor SREBP2 and its target genes are upregulated in various cancers, including liver and breast cancers.23 In addition, Hedgehog and Notch signaling pathways can promote cholesterol synthesis and tumor cell proliferation. Since these genes and signaling pathways can tightly regulate cholesterol metabolism, targeted modulation of the relevant molecular pathways can promote cholesterol uptake and synthesis and reduce its efflux and esterification.24 Increased cholesterol absorption and synthesis can occur in conjunction with increased cholesterol esterification, which is the key to storing excess cholesterol. However, to reduce esterification, it is necessary to regulate the expression or activity of enzymes involved in this process, e.g., acyl-CoA: ACAT. Enhanced cholesterol esterification can lead to pathologic cholesterol accumulation, which is particularly important, for example, in particular cardiovascular diseases or metabolic disorders.25 Therefore, fine-tuning the relevant molecular pathways selectively regulates cholesterol storage and efflux and promotes lipid metabolism homeostasis. This mechanism provides new insights into tumor biology, highlighting the potential effects of cholesterol metabolism in tumor progression.
Studies have shown that dysregulation of cholesterol metabolism is associated with various diseases, particularly cardiovascular and metabolic diseases. For instance, elevated cholesterol levels can lead to atherosclerosis, increasing heart disease risk. Tumor cells often utilize cholesterol as a signaling molecule to promote their growth and proliferation. An in-depth study of the mechanisms of cholesterol metabolism and its role in disease could provide insights for novel preventive and therapeutic strategies.26
Fat drops
Excess free fatty acids are highly toxic to cells; excess fatty acids or cholesterol are generally converted into neutral lipids and stored in lipid droplets. These droplets are involved in lipid storage, metabolism, protein quality control, and immune responses. Disruption of lipid droplet homeostasis impairs lipid metabolism, a phenomenon that is particularly evident in tumor cells.27 Savovic et al. demonstrated that an increase in lipid droplet density promotes the proliferation of colon cancer cells, whereas inhibition of lipid droplet-modifying proteins (e.g., periplasmic lipocalin 2 (PLIN2)) or overexpression of regulatory factors (e.g., FOXO3) suppresses this proliferation. Thus, regulating FOXO3 and lipid droplets could be a novel therapeutic target for colon cancer.28
Lipid droplets are energy reservoirs involved in cell signaling, stress response, and lipid metabolism. PLIN2 affects the relevant metabolic status and proliferation ability of cells by regulating the dynamic balance of lipid droplets. When PLIN2 is inhibited, lipid droplets release free fatty acids, which increase intracellular oxidative stress and metabolic pressure, thus inhibiting the proliferation of tumor cells. FOXO3 directly regulates lipid synthesis and metabolism and restricts tumor cell growth by controlling cell cycle progression and anti-oxidative stress. Overexpression of FOXO3 will limit the growth of tumor cells by inhibiting cell cycle proteins, affecting lipid droplet formation, and controlling cell cycle progression and anti-oxidative stress. FOXO3 can not only directly regulate the synthesis and metabolism of lipids and affect the formation of lipid droplets but also control the cell cycle process and anti-oxidative stress, which can limit the growth of tumor cells. Overexpression of FOXO3 will play a role in inhibiting proliferation by inhibiting cell cycle proteins, activating antioxidant factors, and regulating lipid metabolism, among other pathways. The combination of lipid metabolism, oxidative stress, and cell cycle control is important in tumor biology. Dynamic changes in lipid droplets, fatty acid metabolism, and the integration of intracellular signaling pathways together determine the proliferative capacity of cells. Theoretically, modulation of these pathways can effectively inhibit tumor proliferation, primarily by altering lipid metabolism and activating transcription factors such as FOXO3, which can control the growth trend of tumor cells in multiple directions.
Degradation of lipid droplets occurs through two primary mechanisms: lipolysis and phagocytosis.29 Excessive lipolysis typically increases free fatty acid concentrations in the cytoplasm, promoting fatty acid oxidation in the mitochondria and enhancing reactive oxygen species (ROS) production. These disturbances are detrimental to tumor cells as ROS can induce DNA damage and protein misfolding and activate stress signaling pathways that may promote tumor progression. Hippophagy, a specific form of autophagy identified in recent studies, is generally thought to inhibit tumor growth by promoting the degradation of lipid droplets. However, its role in cancer remains controversial. Some studies suggest that hippophagy might support tumor growth under certain conditions by supplying tumor cells with lipids necessary for membrane biogenesis and energy production. Further research is required to elucidate the potential roles of lipid droplets and their metabolism in tumors and how ROS generation and hippophagy impact tumor cell survival and proliferation.
Antitumor effect of lipids: modulating the tumor immune microenvironment through metabolic reprogramming
Lipids play a critical role in the immune response of tumor cells. In the tumor microenvironment, immune cells meet nutritional and energy needs by upregulating lipid metabolism. The tumor microenvironment comprises tumor cells, immune cells, blood vessels, extracellular matrix, and signaling molecules, and intercellular interactions promote tumor development.30 Unlike normal cells, the rapid proliferation of tumor cells typically relies on their high consumption of glucose, amino acids, and lipids. This consumption suppresses the function of immune cells by depleting nutrients and secreting immunosuppressive substances while limiting the absorption and utilization of nutrients by immune cells.31
Tumor cells produce large amounts of lactic acid during glycolysis, acidifying the tumor microenvironment. At the same time, tumor cells also release fatty acids and adenosine, inhibiting immune cells’ activity. Generally, the rapid division of tumor cells leads to the accumulation of ROS, which in turn causes damage to normal cells. However, tumor cells use these reactive molecules as elements of their metabolic reprogramming. Because tumor cells possess enhanced antioxidant capacity to counteract oxidative stress and protect themselves from ROS-induced damage, they support their own survival and development by altering their metabolic pathways, using ROS as signaling molecules to activate the antioxidant system and increase cell survival in the event of oxidative damage. In contrast, ROS have deleterious effects in immune cells, particularly effector T cells (Teff). Mak et al. found that ROS in T cells inhibit their metabolic reprogramming, impairing their ability to respond effectively to tumor cells and highlighting a key difference in the effects of ROS on tumor cells and immune cells: tumor cells utilize ROS for survival, whereas immune cells are hampered Reczek et al. suggest that tumor cells use ROS as signaling molecules to enhance their antioxidant capacity,32 enabling them to survive and thrive in the harsh tumor microenvironment. The metabolic characteristics of tumor cells allow them to be targeted therapeutic targets; however, their metabolic plasticity makes them susceptible to multi-drug resistance. Metabolic reprogramming, a distinctive feature of cancer, can improve antitumor efficacy by modulating the function of immune cells, in addition to discovering new therapeutic strategies through this pathway.33
Reducing the risk of tumorigenesis by modulating lipid metabolism is a promising approach for cancer prevention and treatment. Tumor cells typically achieve rapid proliferation and migration by altering lipid metabolism pathways. This metabolic reprogramming not only drives tumor development but also remodels the tumor immune microenvironment by regulating the function of immune cells. Therefore, targeting lipid metabolic pathways can inhibit tumor development and offer new strategies for early cancer screening and personalized prevention.34
Lipid metabolism markers and immune responses in the tumor microenvironment
Lipid metabolic markers hold significant promise for early cancer diagnosis and risk prediction by reflecting metabolic changes in tumor cells and their microenvironment.35 These markers cannot only show the characteristics of tumor cells during metabolic reprogramming but also play a vital role in tumorigenesis and progression. Studies have shown that abnormal changes in lipid metabolism can serve as potential early cancer markers while providing a scientific basis for personalized screening, dynamic monitoring, and preventive intervention.36 Furthermore, lipid metabolism markers can elucidate metabolic disorders associated with tumors and guide related therapeutic approaches.
As lipid metabolism research and assay technologies advance, these markers are expected to become important to early cancer screening. They offer new avenues for early detection, precision prevention, and optimized treatment and provide new insights to improve cancer management.37 Relevant lipid metabolism markers are shown in Table 1, and the relevant mechanisms are shown in Figure 1. Mechanisms related to the effect of lipid metabolism on the tumor microenvironment are shown in Figure 2.
Table 1Common lipid metabolism markers
| Lipid metabolism marker | Form | Relevant mechanisms | Application areas |
|---|
| Fatty acid synthase (FAS) | Enzymes | Promote fatty acid synthesis to support tumor cell proliferation and survival | Tumor cell metabolic reprogramming, early diagnosis |
| Fatty acid transporter protein (FATP) | Carbohydrate | Promotes endocytosis of fatty acids and participates in the regulation of cellular energy metabolism | Metabolism-related tumor markers, early screening |
| Cholesterol metabolites (oxysterols) | Metabolite | Promoting cell membrane fluidity and signaling pathways by regulating tumor progression | Relationship between cholesterol metabolism and cancer, precision prevention |
| Ceramide | Lipids | Influence tumor development by regulating apoptosis, inhibiting cell proliferation and other actions | Tumor therapeutic targets, early screening |
| Lysophosphatidylcholine (LPC) | Lipids | Promoting tumor cell growth and tumor cell migration through activation of the PI3K/Akt pathway migration | Prognostic markers, tumor spread prediction |
The regulation of lipid metabolism and the tumor microenvironment is inextricably linked not only to tumor cells but also to various immune effector and immunosuppressive cells, collectively called tumor-infiltrating immune cells. The function of tumor-infiltrating immune cells contributes both to the antitumor response and to the promotion of tumor growth, and the specific role usually depends on the type of tumor and its stage. Tumor-infiltrating immune cells mainly include T cells, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), natural killer cells (NKs), and macrophages.38 These cells promote further tumor development by regulating lipid metabolism and immune responses in the tumor microenvironment.39
Association of abnormal lipid metabolism with tumorigenesis
Tumor cells reprogram their lipid metabolism through various mechanisms, which include enhanced fatty acid synthesis, reduced fatty acid oxidation, increased fatty acid uptake, and altered lipid storage.40 This metabolic reprogramming, on the one hand, can meet the needs of rapid proliferation of tumor cells and, on the other hand, can generate specific signals in the tumor microenvironment, promoting tumorigenesis and progression. Therefore, lipid metabolic profiles may serve as biomarkers for detecting early-stage tumors.41 For example, aberrant expression of cholesterol esterase (ACAT) is usually closely associated with tumor growth, whereas changes in the concentration of fatty acid metabolites in the blood may indicate early tumor development.42 In addition, different types of tumors usually have various lipid metabolism characteristics. Therefore, analysis of lipid metabolism markers not only helps in early diagnosis but also helps to identify specific tumor types.
Lipid metabolism markers are important for early cancer diagnosis and prediction, as well as potential targets for tumor prevention and treatment.43 For example, drugs for the lipid metabolism enzyme SCD1 can alter the metabolic state of tumor cells, thereby inhibiting cancer development. Altering fatty acid intake and metabolism also effectively reduces cancer incidence.44 Targeted intervention strategies for lipid metabolism have far-reaching implications in cancer prevention and treatment, further promoting the application of precision medicine.
T cells in the immune microenvironment
T cells play a crucial role in inhibiting the proliferation and development of tumor cells, enabling them to invade tumor tissues and exert their effector functions.45 CD4+ T cells primarily rely on fatty acid oxidation for energy to adapt to the nutrient-poor tumor microenvironment, and typically, these cells exhibit immunosuppressive effects. CD4+ T cells are a diverse population consisting primarily of effector T cells (e.g., Th1 and Th2 cells) and immunomodulatory cells (e.g., regulatory T cells (Treg)).46 These subpopulations display significant variability in their metabolic profiles and immune functions, particularly in the nutrient-poor tumor microenvironment (TME): Th1 and Th2 cells predominantly rely on fatty acid oxidation (FAO) and aerobic glycolysis to generate energy for adaptation to the TME. Th1 cells are crucial for cellular immunity, typically exhibiting enhanced dependence on FAO, which supports their functions. Th2 cells are implicated in humoral immunity and immunomodulation and upregulate lipid metabolism, but their role is more focused on supporting immune responses against extracellular pathogens. In contrast, Tregs primarily rely on oxidative phosphorylation (OXPHOS) and FAO to maintain their function in the TME. Their metabolic flexibility allows them to thrive in nutrient-poor environments and supports their immunosuppressive activity, enabling them to suppress the effector functions of other immune cells, including tumor-reactive T cells. Metabolic reprogramming of these CD4+ T cell subsets plays a vital role in shaping the immune response within the TME. Effector T cells (Th1/Th2) are typically activated to generate antitumor immune responses, whereas Tregs inhibit these responses, thereby contributing to the immune evasion of tumors. The differential dependence of these subsets on FAO and other metabolic pathways further emphasizes the complexity and diversity of cancer immune responses.
In the hypoxic tumor microenvironment, hypoxia-inducible factor 1α (HIF-1α) is a key regulator that modulates the cellular response under hypoxic conditions. HIF-1α, in cooperation with the receptor protein HIF-1β, upregulates genes related to promoting glycolysis and inhibiting mitochondrial oxidative phosphorylation, thereby facilitating cellular adaptation to hypoxic conditions. This process plays a significant role in the tumor immune microenvironment and is particularly crucial for immune cells, including CD8+ T cells.47 On the contrary, CD8+ T cells mainly rely on aerobic glycolysis for energy, so their function is closely related to the nutritional status of the tumor microenvironment. Studies have shown that tumor infiltration of CD8+ T cells is positively correlated with the prognosis of patients, which is mainly because tumor-specific antigens can cause CD8+ T cells to release effector molecules, such as perforin, which effectively inactivate tumor cells.
Studies have emphasized that nutrients and their associated metabolic processes influence T cell function, with lipid metabolism playing a central role. Lipids regulate intracellular homeostasis through uptake, synthesis, and hydrolysis as key components of cell membranes. By regulating key enzyme nodes in T cell lipid metabolism, the functional properties of T cells can be promoted or inhibited under different conditions. At homeostasis, T cell activation, differentiation, and maturation require different patterns of lipid metabolism. Fatty acids bind to fatty acid-binding proteins on the T cell membrane, facilitating the nuclear localization of fatty acids and activating the nuclear receptor PPAR to participate in transcriptional regulation. In addition, T cells are actively involved in fatty acid uptake and transport. Together, these mechanisms highlight the critical role of lipid metabolism in the antitumor function of T cells and provide new perspectives for future tumor immunotherapy studies.
Dendritic Cells (DC) in the immune microenvironment
Dendritic cells (DCs) are key antigen-presenting cells of the innate immune system, mainly responsible for detecting and processing signals and interacting with T cells, which serve as a bridge between innate and adaptive immunity. Studies have shown that lipid metabolism is pivotal in dendritic cell activation and function. A lipid-rich tumor microenvironment promotes tumor cell growth and proliferation, but this environment of high lipid content impairs the antitumor and immune functions of dendritic cells and limits their ability to activate T cells. Further studies have shown that inhibition of FAO enhances the antitumor function of dendritic cells, suggesting that lipids from tumors (e.g., fatty acids) may also limit the antitumor capacity of dendritic cells. Furthermore, cholesterol metabolism also inhibits dendritic cell function.48 These findings above highlight that tumor cells regulate the lipid metabolism of dendritic cells and can help them adapt to changes in their environment while influencing their role in innate and adaptive immune responses.
By integrating lipid metabolism modulation with immunotherapy, the antigen-presenting capacity of dendritic cells and their subsequent activation of T cells can be significantly enhanced, thereby amplifying their antitumor effects. However, dendritic cells may develop tolerance in the tumor microenvironment, a phenomenon closely related to their metabolic changes.49 Zhao et al. demonstrated that melanoma-derived Wnt5a not only induced tolerance in dendritic cells but also promoted the establishment of an immunosuppressive tumor microenvironment in a primary melanoma model. This finding highlights the importance of metabolic remodeling in the interactions between tumor cells and dendritic cells.50 Investigating the metabolic mechanisms underlying dendritic cell tolerance in the tumor microenvironment is now a crucial approach to modifying the immunosuppressive environment and enhancing tumor immunotherapy. A deeper understanding of these mechanisms allows for designing targeted therapies to improve clinical outcomes more effectively.
MDSCs in the immune microenvironment
MDSCs, an important component of tumor-infiltrating immune cells, are highly heterogeneous immature myeloid cells derived from myeloid progenitor and precursor cells. DScs can be classified into two major subtypes: polymorphonuclear (PMN)-MDSCs and monocyte (M)-MDSCs.51 In the tumor microenvironment, these cells not only inhibit T cell-mediated antitumor responses but also promote angiogenesis, cell invasion, and the establishment of pre-metastatic niches, thereby accelerating tumor progression.52
The immunosuppressive mechanism of MDSCs involves multiple pathways, including nutrient deprivation, induction of apoptosis in immune cells, production of suppressor cytokines, and synthesis of ROS that can disrupt T cell receptor signaling. MDSCs in the peripheral blood and spleen rely primarily on glycolysis for energy, whereas MDSCs in the tumor microenvironment derive energy primarily through enhanced FAO.53 Therefore, targeting the FAO pathway may be a promising strategy to alleviate immunosuppression and improve efficacy.
In addition to FAO, metabolic processes such as fatty acid synthesis, lipogenesis, and lipid accumulation are closely related to the immunosuppressive function of MDSCs.54 Veglia et al. demonstrated that MDSCs transport arachidonic acid via fatty acid transporter 2 (FATP-2) and utilize arachidonic acid to synthesize prostaglandin E2, which leads to the suppression of T cell-mediated antitumor immune response. Inhibition of FATP-2 effectively attenuated the immunosuppressive activity of PMN-MDSCs and significantly delayed tumor development in a mouse model.55
Further studies on the metabolic characteristics and immunosuppressive mechanisms of MDSCs in the tumor microenvironment will provide important theoretical insights and practical guidance for developing novel antitumor therapeutic strategies.
Other immune cells in the immune microenvironment
Natural killer (NK) cells play a crucial role in the antitumor immune response and are often referred to as “rapid first responders”.56 As the frontline defenders against cancer, NK cells induce tumor cell death by releasing cytotoxic substances such as perforin and granzyme B (GzmB) and inflammatory cytokines, including interferon-γ and tumor necrosis factor. However, various factors within the tumor microenvironment, particularly the lipid-rich environment, can impede this process and allow tumor cells to evade immune surveillance.57
Studies have shown that the functionality of immune cells is closely related to their metabolic properties. Thus, maintaining normal lipid metabolism is essential for the proper functioning of NK cells and the immune system as a whole.58 Research on the signaling pathways of lipid metabolism in NK cells remains limited, primarily focusing on the mammalian target of rapamycin (mTOR) and sterol regulatory element-binding proteins. As a key regulator of cellular metabolism, mTOR influences NK cell development and activation. For instance, the knockdown of the CISH gene in NK cells activates the mTOR signaling pathway, enhancing their metabolic adaptation and antitumor abilities.59 A comprehensive study of the lipid metabolic profile of NK cells in the tumor microenvironment will deepen our understanding of the immunosuppressive mechanisms and provide important theoretical support for developing novel antitumor therapeutic strategies.
Macrophages, one of the primary immune cell types in the tumor microenvironment, account for more than half of the total number of cancer cells and play a pivotal role in tumorigenesis and progression.60 Macrophages can have dual roles in anti-inflammatory response and tumor growth promotion and are classified into two phenotypes, M1 and M2, with anti-inflammatory and tumor growth-promoting functions, respectively. M1-type macrophages rely mainly on glycolysis for energy production, whereas M2-type macrophages are characterized by their reliance on FAO.61
Macrophages can rapidly transition from oxidative phosphorylation to aerobic glycolysis while allowing the intermediates of glycolysis to enter the pentose phosphate pathway, resulting in the production of NADPH.62 Oxidative enzymes of NADPH produce ROS by utilizing NADPH. Increased FAO is a key marker in the polarization of tumor-associated macrophages (TAMs) toward the M2 phenotype.63 However, recent studies have revealed a more subtle role for M2-like macrophages, which can promote antitumor immunity under certain conditions. In contrast, FAO has been identified as a key metabolic pathway that promotes M2-like macrophage function, particularly in terms of their ability to secrete pro-inflammatory cytokines such as CXCL10, IL-1β, and IL-10.64 These cytokines are associated with inflammation and can have complex effects on the tumor tissue mesenchyme.
In some cases, cytokines secreted by M2 macrophages can enhance the cytotoxicity of effector T cells (Teff) and NK cells, promoting antitumor immunity. This phenomenon suggests that M2 macrophages may play a positive effect in enhancing tumor immune responses. Its aspect is by promoting the activation of immune effector cells. The dual role of M2 macrophages is evident when they are involved in both immune activation and immunosuppression. In some cases, particularly when tumor tissues and organs exhibit chronic inflammation or immune evasion, M2 macrophages promote tumor development by producing immunosuppression through the secretion of cytokines such as IL-10 and TGF-β, which inhibit the activity of antitumor immune cells, allowing tumors to evade immune surveillance and grow rapidly. This paradoxical behavior shows the complexity and diversity of M2 macrophage functions in TME. In TME, they can shift between promoting immune activation and promoting immune suppression depending on the relevant signaling cues and the metabolic environment in which they operate.65 Therefore, a comprehensive understanding of the metabolic characteristics of macrophages in the tumor microenvironment and the mechanisms underlying their phenotypic polarization could provide an important theoretical basis for developing novel antitumor therapeutic strategies. This will help elucidate the mechanisms of tumor immune escape and potentially guide immune interventions in clinical therapies.
Cancer screening, prevention, and tumor immunotherapy
Tumor immunotherapy aims to restore the body’s immune defense against tumors by modulating the function of the immune system.65 This approach encompasses various strategies, including immune checkpoint inhibitors, T-cell transfer therapies, monoclonal antibodies, and immunomodulators. The efficacy of immunotherapy is closely related to the immune regulatory mechanisms in the tumor microenvironment, which in turn are influenced by the lipid metabolism of immune cells.66 Therefore, combining the lipid metabolism of immune cells in the tumor microenvironment with immunotherapy has become a key approach to controlling tumor growth.
Studies have demonstrated that reprogramming of lipid metabolism drives tumor cell proliferation and metastasis and affects immune escape mechanisms by modulating immune cell function. This insight provides new perspectives for the early screening and prevention of cancer.
Lipid metabolism and cancer screening, prevention
Primary lipid metabolites such as fatty acids, cholesterol, and fatty acid synthase in blood or tumor tissues serve as principal biomarkers for the early diagnosis of cancer.67 Changes in the concentrations of these metabolites reflect the progression of tumor cell development and provide a valuable reference for early cancer screening. Moreover, dysregulated lipid metabolism affects both the behavior of tumor cells and the function of immune cells in the tumor microenvironment. For instance, abnormal lipid metabolism regulates the state of the tumor microenvironment by suppressing the immune response of Th1 cells, inhibiting the function of dendritic cells and MDSCs.
Analyzing lipid metabolism markers in immune cells offers insights into the state of the tumor immune microenvironment. This approach provides a new reference for screening and efficacy monitoring of immunotherapy and reveals new targets for cancer screening by regulating lipid metabolism or using lipid metabolism markers to monitor tumor immune escape. Additionally, interventions targeting lipid metabolism represent an effective cancer prevention strategy. For example, inhibiting fatty acid synthesis pathways or promoting FAO can slow tumor growth, reducing the risk of cancer development.68
In conclusion, lipid metabolism markers not only play a crucial role in the early diagnosis and screening of cancer but also open new pathways for advancing immunotherapy for tumors and developing effective cancer prevention strategies.
Lipid metabolism and immunotherapy
Various tumor treatments targeting lipid metabolism have shown promising clinical effects. For example, the uptake of exogenous fatty acids by tumor cells largely depends on the expression of CD36, so the clinical application of CD36 inhibitors can effectively inhibit the proliferation of tumor cells; in addition, its combination with FASN inhibitors and anti-PD-1 therapies can also produce synergistic effects. In addition to the function of tumor cell clearance, CD36 can also improve the immunosuppressive environment in the tumor microenvironment.69
Fatty acid metabolism plays a significant role in tumor-associated immune cells. Therefore, modulation of fatty acid metabolism reduces the immunosuppressive effects of tumor cells.70 Once the metabolic blockage is alleviated, tumor-associated immune cells can shift from a tumor growth-promoting phenotype to a tumor growth-suppressing phenotype, which enhances their ability to eradicate tumors. In addition, cholesterol plays an integral role in tumor immunotherapy by not only dog directly affecting the growth and proliferation of tumor cells but also acting as a drug delivery vehicle (e.g., liposomes, lipid nanoparticles, and lipid vesicles) to enhance its drug delivery efficiency in the tumor microenvironment while also minimizing side effects.71
Iron mutation is an iron-dependent form of regulatory cell death. It was first described by Stock Well and colleagues in 2012. Iron death is primarily triggered by the toxic accumulation of peroxides of lipids within the cell membrane. Thus, it is distinct from conventional forms of cell death. Morphologically, iron pituitary disease is mainly characterized by mitochondrial contraction, increased membrane density, and cell membrane rupture, a unique form of cell death that shows great potential for cancer therapy.
TMEs, particularly immune cells, are crucial in inducing iron-jumping in tumor cells.CD8+ cytotoxic T cells inhibit cystine uptake by tumor cells and promote iron oxidation through interferon-gamma secretion, which down-regulates the transporter SLC7A11.CD8+ cytotoxic T cells are known for inhibiting cystine uptake and promoting iron oxidation in tumor cells. In addition, specific immunosuppressive cells, such as regulatory T cells (TREGs)-a subpopulation of CD4+ cells-that impede their immunosurveillance of tumor cells can also exhibit their resistance to ferritin deposition.72
Despite the great potential of iron apoptosis as a metabolically regulated form of cell death in cancer therapy, understanding its underlying mechanisms remains incomplete. Further studies are still needed to investigate whether the activation of iron apoptosis inhibits tumor cell progression and how it affects the sensitivity to immune checkpoint therapy.73 Because tumor cells are intrinsically or acquired resistant to ferritin deposition, targeting these cells with resistance mechanisms is expected to enhance their sensitivity to this form of cell death. Therefore, to fully utilize the potential of iron apoptosis in cancer therapy, future studies must intensify the exploration of this area.72
In conclusion, lipid metabolism plays a crucial role in the development and treatment of cancer. As a fundamental component of normal cells, abnormal lipid metabolism has become critical for cancer treatment. Characterizing lipid metabolism in the tumor microenvironment provides a novel perspective for early cancer screening and prevention, whereas lipid metabolism reprogramming is also expected to be a biomarker for early cancer diagnosis. Therefore, a comprehensive exploration of the interactions between lipid metabolism and the tumor immune microenvironment will deepen our understanding of the molecular mechanisms of tumorigenesis and provide a solid theoretical foundation and precise practical guidance for developing new cancer screening, prevention, and treatment strategies.
Future prospective
The tumor microenvironment represents a complex ecosystem where lipid metabolic interactions between cancer cells and immune cells play a pivotal role in cancer development. Tumor growth and proliferation depend not only on the supply of energy and nutrients but also on the intricate processes of lipid metabolism. Lipids in the tumor microenvironment can suppress immune responses or enhance antitumor immunity by promoting immune cell activity. Disrupting lipid metabolism can confer growth advantages to tumor cells, fostering tumor progression and resistance to treatment.
Lipid-derived messenger molecules regulate multiple signaling pathways, influencing tumor cell proliferation, differentiation, migration, and invasion while impacting immune cell function and potentially orchestrating tumor immune escape. Appropriately modulating lipid metabolism may offer a promising strategy for cancer therapy. Additionally, various markers of lipid metabolism play significant roles in tumor progression and could serve as diagnostic and predictive biomarkers. The relationship between lipid metabolism and ferroptosis is an emerging area of interest. Alterations in lipid metabolism may affect tumor cell sensitivity to ferroptosis, showing its potential as a therapeutic target.
Despite the promising therapeutic potential, strategies based on lipid metabolism face challenges, such as the clinical translation of lipid metabolism markers and the optimization of lipid drug delivery systems. Future research should focus on developing feasible lipid metabolism markers that accurately reflect the metabolic status of tumors, optimizing lipid drug delivery through carriers such as liposomes and nanoparticles, and integrating immunotherapeutic strategies. For instance, CD36 inhibitors can reduce lipid uptake by TAMs, alleviating immunosuppression and enhancing antitumor immunity. Combining CD36 inhibitors with immune checkpoint inhibitors might offer a synergistic treatment approach.
A comprehensive study of lipid metabolism in tumorigenesis and treatment will propel advances in early diagnosis, precision therapy, and effective cancer prevention, offering new insights and practical guidance for future cancer research.
Conclusions
Lipid metabolism is integral to tumor development and immune regulation. Understanding its mechanisms can lead to novel therapeutic strategies, early diagnosis, and improved treatment outcomes for cancer. Continued research is essential to refine lipid-based interventions and optimize their clinical applications.
Declarations
Funding
No funding was received for the study.
Conflict of interest
One of the authors, Prof. Rui Hua Shi, has been an associate editor of Cancer Screening and Prevention since February 2022. All other authors have no conflict of interest related to this manuscript.
Authors’ contributions
XSL contributed to the study concept and design, and drafted the manuscript; LHR performed the critical revision of the manuscript; and RHS supervised the study.