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Lipid metabolism associated crosstalk: the bidirectional interaction between cancer cells and immune/stromal cells within the tumor microenvironment for prognostic insight

Cancer Cell International volume 24, Article number: 295 (2024) Cite this article

Abstract

Cancer is closely related to lipid metabolism, with the tumor microenvironment (TME) containing numerous lipid metabolic interactions. Cancer cells can bidirectionally interact with immune and stromal cells, the major components of the TME. This interaction is primarily mediated by fatty acids (FAs), cholesterol, and phospholipids. These interactions can lead to various physiological changes, including immune suppression, cancer cell proliferation, dissemination, and anti-apoptotic effects on cancer cells. The physiological modulation resulting from this lipid metabolism-associated crosstalk between cancer cells and immune/stromal cells provides valuable insights into cancer prognosis. A comprehensive literature review was conducted to examine the function of the bidirectional lipid metabolism interactions between cancer cells and immune/stromal cells within the TME, particularly how these interactions influence cancer prognosis. A novel autophagy-extracellular vesicle (EV) pathway has been proposed as a mediator of lipid metabolism interactions between cancer cells and immune cells/stromal cells, impacting cancer prognosis. As a result, different forms of lipid metabolism interactions have been described as being linked to cancer prognosis, including those mediated by the autophagy-EV pathway. In conclusion, understanding the bidirectional lipid metabolism interactions between cancer cells and stromal/immune cells in the TME can help develop more advanced prognostic approaches for cancer patients.

Graphical Abstract

Introduction

Cancer has been widely indicated to be one of the most fatal diseases in the world. In cancer patients, metabolic processes are significantly altered. Lipolysis, fatty acid oxidation (FAO), and glycolysis have been indicated to play key roles in the reprogramming of cancer cell metabolism, which in turn impacts the prognostic outcomes of cancer patients [1]. Among various metabolic subtypes, lipid metabolism is crucial to play key roles in many physiological functions and is linked cohesively to cancer prognosis. Lipids can be categorized into several groups based on their molecular characteristics, including phospholipids, fatty acids (FAs), cholesterol, etc. These metabolites can serve as intermediates between cancer cells and the components of the tumor microenvironment (TME). The TME comprises cancer cells, immune cells, stromal cells, signaling molecules, the extracellular matrix (ECM), and blood vessels, The TME is characterized by hypoxia and acidosis, which can stimulate angiogenesis and metabolic reprogramming. Under the influence of lipid metabolism programming, cancer cells increasingly interact with the immune/stromal cells of the TME using lipid metabolic intermediates [2,3,4]. Moreover, a novel autophagy-EV pathway in the TME has been proposed by studies [5, 6]. In this pathway, EVs containing the lipid metabolites can be secreted from cancer cells and immune/stromal cells by a pathway related to autophagy, integrating autophagy into the complex lipid metabolism network.

The lipid metabolic modifications in the TME, induced by the interaction with cancer cells, can have an impact on cancer prognosis by reducing immunity, increasing angiogenesis, or promoting tumor cell growth [7, 8]. Interestingly, the metabolic reprogramming in the immune cells and stromal cells in the TME, mediated by the modified lipid metabolism in the TME triggered by cancer cells, are also capable of inversely affecting cancer prognosis. This intricate relationship can be prosperous for cancer prognosis.

Although the TME has been studied in many aspects regarding its compact relationship with cancer prognosis, no current systemic description of how cancer cells can affect the behaviors of other TME cellular components, which could be the key to cancer prognosis, has been published. Several reviews discussing about the FA metabolism in cancer, but the holistic relationship of how FA affect cancer prognosis bidirectionally between cancer cells and immune/stromal cells, and how the specific autophagy-EV pathway can affect FA metabolism between these cellular components, has yet to be discussed [9]. The significance of this review lies in elucidating the correlation between autophagy-EV pathway and stromal/immune cells in the TME, where lipid metabolism plays a key role. Understanding these intricate relationships can inspire novel prognostic tools. This review will describe how modifications in the lipid milieu, exerted by cancer cells in the TME, influence other cellular components, as well as the role of the autophagy-EV pathway.

General mechanism of how cancer cells convey the modification of lipid milieu in the TME and how the autophagy-EV pathway is conducted

The TME comprises cellular and non-cellular components, each significantly impacting cancer prognosis. The cellular components of the TME include a diverse array of immune cells like T-cells, B-cells, natural killer (NK) cells, macrophages, neutrophils, and dendritic cells. These immune cells have been indicated to have effects on cancer prognosis by the increase or suppression of their immunities by the modified lipid metabolism in the TME, as will be illustrated in the following context. Additionally, the TME contains structural and functional supporting cells: stromal cells such as endothelial cells, cancer-associated fibroblasts (CAF), adipocytes, and stellate cells [3]. These stromal cells interact with immune cells and cancer cells, and are capable of affecting cancer prognosis by influencing tumor growth and metastasis, and angiogenesis. Figure 1 has displayed these interactions.

Fig. 1
figure 1

Diagrammatic presentation of the lipid mediated interaction between cancer cells and cellular components of the TME. Cancer cells can influence the lipid composition of the TME and therefore influence stromal and immune cells. Simultaneously, stromal and immune cells can also affect cancer cells using those lipid metabolites, further affecting cancer prognosis

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Non-cellular components include the ECM and EVs [3]. The ECM is an intricate network of bioactive proteins that construct a stable complexity, thus playing a role in the mechanical properties of the TME [10]. Interestingly, mechanical property modifications in the TME can modulate the activity of Lipin-1 phosphatidate phosphatase [11]. Lipin-1 phosphatidate phosphatase plays a crucial role in lipid metabolism by converting phosphatidate to diacylglycerol, a key step in the synthesis of triglycerides and phospholipids [12]. This modulation has been proven to assist in colon carcinogenesis, particularly when facilitated by inflammation [13]. Additionally, Sterol Regulatory Element Binding Protein 1 (SREBP-1), a transcription factor that regulates the expression of genes involved in lipid biosynthesis [14], has been indicated as a prognostic marker, which promotes the progression of breast cancer [15].

Conditions of reduced actomyosin contractility generated by the ECM can result in the inhibition of Lipin-1, buildup of SREBP within the Golgi apparatus, and arousal of SREBP transcription factors, consequently propelling lipid production and aggregation [11]. This relationship shows that reduced actomyosin contractility generated by the ECM can be a good prognostic marker for colon cancer but a poor marker for breast cancer. Specifically, in breast cancer, the propelled lipid production could be linked with poor prognosis of breast cancer, given that the buildup of SREBP increases lipid production and SREBP-1 can promote breast cancer progression.

How cancer cells influence the lipid milieu of the TME

In cancer cells, altered lipid metabolism pathways are exhibited to meet their increased energy and biosynthetic needs. The specific metabolic alteration can affect the lipid milieu of the TME, in combination with rapid growth of cancer cells and inadequate blood supply for the TME [16].

Tumor cells tend to present altered lipid metabolism characterized by enhanced fatty acid (FA) synthesis, FA uptake and exchange, increased cholesterol synthesis and accumulation, altered phospholipid synthesis, abnormal levels of FASN (fatty acid synthase), and unregulated lipogenesis, especially within the TME [17]. Specifically, FA synthesis is often increased in cancer cells through the upregulation of de novo FA synthesis pathways, where enzymes such as FASN and ATP citrate lyase (ACLY) can play a key role [18, 19]. Tumor cells also show increased uptake of FAs from the TME, presumedly through expressing high levels of Fatty Acid Translocase (FAT) /Cluster of Differentiation (CD) 36 and Fatty Acid Binding Protein (FABP), which are capable of facilitating the uptake FAs from the TME [20, 21]. Cancer cells also have an increase in cholesterol synthesis and accumulation by de novo cholesterol biosynthesis that can be driven by the upregulation of the mevalonate pathway [22], where key enzymes like 3-hydroxy-3-methylglutaryl-coenzyme A reductase and squalene epoxidase play pivotal roles, Moreover, tumor cells are capable of absorbing cholesterol from adjacent cells by endocytosis, in which low-density lipoprotein (LDL) plays a role, or by the selective uptake pathway, where high-density lipoprotein (HDL) plays a role. Notably, tumor cells can also export intracellular cholesterol [22]. Altered phospholipid synthesis typically involves the upregulation of choline kinase alpha in the Kennedy pathway, leading to increased production of phosphatidylcholine [23]. The metabolic alterations of phosphoglyceride, the most predominant phospholipids forming cellular membrane in cancer cells, can be linked to the disruption of the enzymes controlling the rate of the phosphoglyceride metabolism and can be key to tumor progression [24].

Through the increased amount of lipid intake, cancer cells can rewrite the lipid environment of the TME. Metabolic competition between cancer cells and stromal cells or immune cells in the TME has been confirmed: One study has pointed out that the elevated glucose consumption by tumor cells can damage the glycolytic quantity and Interferon (IFN)γ manufacturing of T cells, undermining their immunity [25]. Further, cancer cells can deprive FA directly from other cells in the TME to supple their metabolism: A notable example can be breast cancer cells absorbing FA from adipocytes and increase their progressive and metastatic capability [16]. The increased consumption of free FA from the environment of the TME may cause the decreased amount of FA in the TME for other cellular components, leaving insufficient FA for stromal cells and immune cells in the TME. However, most of the time the free FA in non-cellular portion of the TME is higher than normal and the TME is lipid-rich, due to lipolysis from adipocytes and the higher demand for lipid from cancer cells [16].

The uptake of cholesterol to cancer cells or efflux of cholesterol from cancer cells can both significantly impact on stromal/immune cells in the TME. Notably, the metabolites of cholesterol are involved in the manipulation among various pathways found in either cancer cells or immune cells [26]. These pathways demonstrate that cancer cells can regulate immune cells in the TME, influencing cancer prognosis.

Further, some tumor cells may not only exhibit higher phospholipid synthesis than normal cells, they may also have their phospholipase activity regulated. As a study has indicated: Group-II phospholipase A2 is recognized for its specific activity on phosphatidylethanolamine (PE), rather than on phosphatidylcholine, which is the main phospholipid found in the outer layer of human cell membranes [27]. In stomach cancer, Group-II phospholipase A2 is increasingly expressed in poorly dofferentiated cancer cells [28]. Group-II phospholipase A2 can also induce inflammation through arachidonic acid production in cancer cells. Moreover, Group-II phospholipase A2 can enhance inflammation signals, due to its specificity on PE that induced this enzyme to act on extracellular mitochondria found on large EVs [29]. This inflammation process can cause tumor progression and cancer cell proliferation [30]. The increased expression level of phospholipase in cancer cell membrane maybe linked to the phospholipid breakdown of adjacent stromal/immune cells, even disrupting their signaling pathways. Although there is currently no direct evidence how phospholipid or phospholipase from cancer cells can modify the phospholipid metabolism in stromal/immune cells in the TME, the interaction of phospholipid between cancer cells and stromal/immune cells in the TME warrants further exploration and may contribute to cancer prognosis.

The mechanisms of the biogenesis of EVs and the novel autophagy-EV pathway

Autophagy is a degradational process originating from lysosomes, present in all cellular components of the TME. Autophagy retains homeostasis and cellular viability by metabolizing and breaking down cellular components, including durable proteins and debilitated organelles for reusage [5]. EVs play a crucial role in various biological processes within the TME. They contribute to processes such as angiogenesis, immune evasion, and metastasis [31]. EVs are also being explored for their potential to be diagnostic biomarkers and transporters for targeted drug delivery [32]. There are 3 subtypes of EVs found to highly correlated to cancer: exosomes, microvesicles, and large oncosomes [33]. Notably, under some specific circumstances, large onconsomes can play equal important roles as exosomes [34].

The biogenesis of microvesicles include the outward budding of the plasma membrane and the detachment of the membrane vesicle [35]. Microvesicles can selectively incorporate proteins, lipids, and nucleic acids [36]. Oncosomes were first described to be able to facilitate the transfer of EGFR (epidermal growth factor receptor)vIII between glioma cells intercellularly [37]. The biogenesis of large oncosomes also includes the outward budding of the plasma membrane and the detachment of the membrane vesicle. Large oncosomes transport various bioactive molecules, including lipids, from the parent tumor cell [33]. Notably, large oncosome-like vesicles were discovered in CAFs but not in biologically normal fibroblasts [38].

Exosomes originate from endosomes in all cell types in the TME. The fusion between autophagosomes and multivesicular bodies that give rise to exosomes can produce amphisomes containing content of autophagosomes, thus secreting what needs to be autophagized, including lipid that can further influence other cells in the TME [39]. This process is illustrated in Fig. 2. Exosomes are secreted to participate in intercellular communication via the conveying of active biologically active molecules, including proteins, lipids, RNAs, DNA and microRNAs [36].

Fig. 2
figure 2

Simplified diagrammatic presentation that shows the biogenesis of exosomes. Multivesicular bodies responsible for the secretion of exosomes into the extracellular environment can also fuse with autophagosomes, which can fuse with lysosomes to be degraded, also known as autophagy. The fusion between autophagosomes and multivesicular bodies generates amphisomes, which can also secret exosomes into the TME

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The EV-autophagy pathway includes metabolic interaction between cancer cells and immune/stromal cells mediated by EVs and autophagy in cancer cells or immune/stromal cells, as Fig. 3 shows. Specifically, in the TME, lipid components in tumor cells or immune/stromal cells in the TME can be abnormally metabolized by the modification of the novel autophagy-EV pathway to further interfere cancer prognosis [39]. This novel autophagy-EV pathway can contribute to possible lipid metabolic modification, no matter in tumor cells or cellular components like immune cells or stromal cells in the TME, contributing to the complex interaction between cancer cells and components of the TME. Notably, in this pathway, EVs and autophagy can actually play a role on each other: EVs can initiate autophagy within cells; autophagy can participate in the generation and recycling of EVs [5, 39].

Fig. 3
figure 3

Simplified diagrammatic presentation that shows the novel autophagy-EV pathway. The lipid in the EVs secreted from the autophagy-EV pathway can mediated the interaction between cancer cells with immune/stromal cells in the TME and possibly trigger autophagy processes in these cells and affect cancer prognosis

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How stromal cells participate in the lipid metabolic bidirectional Interaction and the autophagy-EV Pathway

Stromal cells play a fundamental role in maintaining tissue homeostasis and providing support for parenchymal cells, with lipid metabolism being an integral part of this process [40]. In the TME, stromal cells are affected by components of the TME and cancer cells, whose effect can in turn influences cancer cells and cancer prognosis.

Adipocytes

Adipocytes provide a source of FAs for tumor cells. Changes in lipid metabolism in the TME within the adipocytes, can be indicated to be associated with more aggressive tumor behavior, progression, and resistance to chemotherapy and targeted therapies [24]. They can be an important source of EVs, which can contribute to the production and regulation of FAs in the TME [41]. Adipocytes can undergo phenotypic modification to become CAFs, through glycerol and free FA generation via cellular and chemical lipid modification [42]. They can be regulated by cancer cells: The regulation of FA metabolism in tumor cells can lead to an aberrant lipid signaling milieu, such as cancer cachexia, which can trigger adipocyte dedifferentiation characterized by pro-inflammatory cytokines. These cytokines can be associated with growth factors in the tumor-surrounding adipose tissue of cachectic patients, indicating angiogenesis and metastasis [43]. Moreover, multiple myeloma cells can initiate lipolysis in adipocytes in the TME and deprive FA via FA transporter proteins [44]. Concurrently, the modified cholesterol metabolism from cancer cells in the TME can cause the dysregulation of adipocyte lipid rafts, which can play a pivotal role in the process of 3T3-L1 adipocytes absorbing long-chain FA [45, 46]. In addition, leptin, significant in the apoptosis and adipogenesis of adipocytes, is capable of regulating macrophage immune effects in cancer cells via pro-inflammatory cytokines and chemokines, highlighting the intricate relationship between leptin, immune responses, and cancer prognosis [47, 48]. Furthermore, adipocytes can have impact on the phospholipid tissue. Elevated levels of phospholipids in various cellular compartments of MDA-MB-231 breast cancer cells grown in medium conditioned by adipose tissue have been observed, linking adipocytes to breast cancer prognosis [49].

Adipocytes are also involved in the autophagy-EV pathway: Cancer cells can activate autophagy in adipocytes via EV secretion in cancer cachexia. EVs developed from cancer cells are capable of triggering cAMP (cyclic Adenosine Monophosphate)/PKA (Protein Kinase A) signaling and a specific autophagy called lipophagy in adipocytes, which tears apart lipid molecules using lysosomes, resulting in the lipolysis and browning of white adipocytes [50]. The resulting adipose tissue loss can be demonstrated as unpromising outcomes in individuals suffering from stomach cancer [51]. The complex interactin between cancer cells and adipocytes via lipid metabolism is presented in Fig. 4.

Fig. 4
figure 4

Lipid-metabolism associated interaction between cancer cells and adipocytes. Cancer cells and adipocytes have shown to interfere with each other via EVs, free FAs, and cholesterol as indicated in the diagram. Phospholipid have played an indirect part, which is not presented on the diagram. Notably, adipocytes can be modified into CAFs, further complexing its role in the TME

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Fibroblasts

The TME is normally replete with CAF. They can engage in lipid storage and mobilization, impacting the TME’s metabolic landscape, and even the cancer cell lipid metabolic profile. Specifically, they are capable of regulating lipid metabolism of cancer cells by stiffening and fibrosing ECM [52, 53]. CAFs are also indicated to regulate FASN expression in cancer cells. This regulation can be mediated by estrogen and may utilize G Protein-coupled Estrogen Receptor as a transduction mediator [54]. Moreover, CAFs have been detected to have its lipid metabolism reprogrammed, with facilitation of the migration of cancer cells [55]. PTEN (Phosphatase and Tensin Homolog) gene, CAF, and prostate cancer cells have been intricately related: the multityrosine kinase inhibitor sorafenib has proven not to be effective in prostate cancer cell cultured with fibroblasts [56]. The PTEN-knocked-out fibroblasts can have malfunctioned mobility. In PTEN-deficient prostate cancer cells, LD volume can be supplemented via the extraction of lipids externally [57, 58]. This leads to the doubt whether CAF can promote lipid absorption from the TME in PTEN-deficient prostate cancer cells. CAF can worsen the prognostic outcome of patients with peritoneal metastatic colorectal cancer by oxidizing FAs via increasing the intracellular expression of CPT1A, a rate-limiting enzyme of FAO. The increased expression of CPT1A in CAFs can promote colon tumor metastasis and progression [59]. The dysregulation of cholesterol metabolism from cancer cells also influences the lipid raft composition in CAFs [46]. FAPα, a kind of protein found on the surface of CAFs, can assemble in lipid rafts and invadopodia in solid tumors and is confirmed as a part of solid tumors, further augmenting tumor-promoting capabilities of CAFs [60]. Notably, PC with unsaturated acyl chains could be favored in the CAF-conditioned medium in colorectal cancer cells, signifying unpromising prognosis for certain patients [61]. The level of SCD in cancer cells can be increased by transferred CAF-derived oleic acid, resulting in elevated lipid metabolism, revealing SCD expression as the marker for poor cancer prognosis [62]. Interestingly, the expansion of lung tumors is associated with a reduction in LD in CAFs and poor prognosis of lung cancer patients [63]. Notably, SCD1 and LD work together in the TME towards the goal of poor prognosis in cancer patients. SCD1 inhibition in CAFs has been validated to reduce the spread of lung tumors. Specifically, several studies have indicated that increased SCD level in cancer cells assists more viable cancer cell proliferation, and even a shift toward a more aggressive tumor phenotype [63, 64]. SCD here is presented to be significant in both CAFs and cancer cells, leading to hypothesis that SCD may also be a bridge through which CAFs can influence cancer cells.

CAFs are involved actively in the autophagy-EV pathway: Oxidized ATM (Ataxia telangiectasia-mutated), which can be augmented by the cholesterol in LDs in CAFs, can initiate the phosphorylation of bcl2 19 kDa Interacting Protein (BNIP) 3. BNIP 3 can initiate autophagy and EV release from breast CAFs. Blockage of oxidized ATM kinase or elimination of ATM or BNIP3 in the cells prevents autophagy and EV release from breast CAFs [65]. Interestingly, protein G Protein-Coupled Receptor 64 related to autophagy is increased in EV originated CAFs, capacitating breast cancer cells more aggressive and metastatic characteristics [65]. This indicates that the cholesterol in the CAF might be able to indicate poor prognosis via the autophagy-EV pathway.

Oncosomes can also participate in this autophagy-EV pathway: miR-409-3p regulates FA binding protein 4, which can substantially increase the metastatic potential of cancer cells in ovarian cancer cells [66]. Expression of miR-409 in normal prostate fibroblasts leads to the phenotypic modification into CAFs. CAFs can further transport miR-409 via oncosomes to cancer cells to promote cancer progression [38]. However, increased miR-409-3p levels can facilitate the chemosensitivity of oxaliplatin, as well as restrain Beclin-1, which is a protein capable of facilitating cancer cell autophagy, by binding to the gene that encodes it [67]. From this pathway, it can be observed that miR-409-3p, which can regulate lipid metabolism, can be transported by oncosomes between cancer cells and CAFs to affect cancer prognosis.

Other

Tumor endothelial cells in the TME may alter lipid metabolism via genetic and transcriptomic modifications to support angiogenesis compared with normal endothelial cells. Their relationship to immune cells has been illustrated to be significant [68]. FAs are highly modified in cancer cells. FA carbon is essential for the supplement of dNTP rather than ATP in endothelial cells, providing further insight into the possible modification direction designed by cancer cells for TECs in the TME [69]. Enhanced FA synthesis and uptake in tumor cells, may lead to an increased production of prostaglandins and leukotrienes as the increased intake of FA dietarily. Prostaglandins and leukotrienes can trigger angiogenesis, which is capable of facilitating endothelial cell proliferation and migration, facilitating tumor growth and metastasis [70,71,72]. The modulation of cholesterol metabolism in tumor cells may generate derivatives such as oxysterols, which is capable of preventing the disease-favorable reactions of endothelial cells in cancer, leading to possibly good prognosis in breast cancer patients [73, 74]. Furthermore, the metabolic interruption of lysophosphatidic acid (LPA) and PS by tumor cells can modify endothelial cell barrier integrity and the release of angiogenic factors, thus showing that LPA and PS may serve as promising indicators of cancer prognosis [75, 76]. Moreover, TEC and adipocytes can produce FA binding protein-4, which can play a key role in tumor relapse together with SCD1 secreted by cancer cells [77]. Interestingly, endothelial cells are annotated in another study to be capable of being activated by FASN, another component of the TME that can play a key role in the FA synthesis in cancer cells, modifying the expressional dynamics and bioavailability of angiogenic factors [78]. The suppression of FASN activity, which can precede VEGF (Vascular Endothelial Growth Factor)-A and other upstream angiogenic routes, is also postulated to be an innovative approach to extrapolate more personalized prognosis of colorectal cancer [78].

Stellate cells can influence the lipid metabolism of the TME, and facilitate liver tumor metastasis especially under acidic environments [79]. Increased levels of FAs from tumor cells in the TME can induce more intensified inflammatory responses in human pancreatic stellate cells (PSCs), which have been observed in pancreatic ductal adenocarcinoma patients [80]. In rodent HSCs (hepatic stellate cells), SCD expression, indicative of worse prognosis, can be upregulated. MUFA produced in that process can facilitate tumor growth. More specifically, within rodent HSCs, SCD expression is regulated by WNT-β-catenin signaling, with MUFAs produced by SCD establishing a positive feedback loop to enhance WNT signaling through the stabilization of Lrp5 and Lrp6 mRNAs, assisting in the progression of liver fibrosis and the expansion of tumor cells [64, 81]. Phospholipid can also interact with stellate cells in the TME. Sphingosine Kinase can be inhibited by endothelin (ET)-1 in Human HSCs. Phospholipids like dimethylsphingosine (Inhibitors of Sphingosine Kinase 1 that are reported to be effective in triggering cancer cell apoptosis and have improved the efficacy of therapy in lung cancer), and threo-dihydrosphingosine, are able to undermine the physiological impact of ET-1, by about 50%, in ELT3 cells derived from Eker rat leiomyoma [82,83,84]. This intricate relationship reveals that phospholipids like dimethylsphingosine and threo-dihydrosphingosine may undermine ET-1 in HSC and provide a possible prognostic perspective.

How Immune cells participate in the lipid metabolic bidirectional Interaction and the Autophagy-EV Pathway

The TME is a highly complex landscape orchestrated by a diverse array of immune cells. Immunology plays a pivotal role in cancer prognosis, and is greatly affected by the reprogrammed lipid metabolism in the TME. In this part, how the tumor cells can influence the immune cells of the TME, and how the influence can further have effect on cancer prognosis will be discussed.

T-cell

T-cells play a significant role in the TME, characterized by cytokines capable of suppressing tumor progression, and its cytotoxic function [85]. Enhanced FA synthesis of tumor cells in the TME can generate a lipid-rich environment that is immune-unfavorable, especially targeting T-cells. The T-cell specified immune suppression irritated by cancer cells is characteristic. For example, deletion of SREBPs normally responsible for FA synthesis in T cells in lipid rich-environment, may cause immune suppression of Teffs [86]. T-cell exhaustion triggered by lipid accumulation, especially cholesterol accumulation from cancer cells, is capable of reducing T-cell anti-tumor activity. Increased cholesterol levels can interrupt T-cell receptor (TCR) signaling, suppressing T-cell immunity, probably by attaching to the transmembrane region of TCRβ or interfering with TCR multimer formation, thereby inhibiting T-cell receptor signaling [87]. T-cells can also be presented less antigens by dendritic cells because of the modified lipid metabolism profile triggered by human mesothelioma tumor cells, due to human monocyte-derived dendritic cells divulged to human mesothelioma tumor cells presenting mounted lipid levels [88]. A decrease in immunogenic cell death and infiltration of CD8 + T cells in metastatic tumors of colorectal cancer patients is linked with the accumulation of LDs (lipid droplets) from colorectal cancer cells [89].

Interestingly, some subtypes of T-cells may inversely affect the immunological capacities of each other. FA can be absorbed by Teffs in the TME, making the immune favorable Teffs increase their viability in the TME. Treg is characterized by its immunosuppressant capability and often found to be upregulated in the TME. Recent study shows that FAO suppression can increase Treg affluence. In both scenarios, FAs play a key role, indicating cancer cells may participate in the phenotypic regulation of T cells in the TME [90, 91].

T-cells can possibly participate in an autophagy-EV pathway: The proportion of programmed death ligand 1 (PD-L1) + TAMs (Tumor-associated macrophages) in the TME of epithelial ovarian cancer increased exponentially, and EVs enriched with PD-L1 + produced by TAMs influence the transcription factor proliferator-activated receptor α (PPARα) in order to enhance the expression of carnitine palmitoyltransferase IA (CPT1A) in CD8 + T cells, stimulate FA oxidation, and generate reactive oxygen species to result in cellular disruption [92]. Consequentially, the apoptosis of CD8 + T cells was initiated, causing immune suppression and cancer metastasis. Notably PD-L1 also participates in anti-T cell activities in other cancer types. In gastric cancer, tumor cells can promote TAM lipid accumulation, further increasing their PD-L1 expression and prohibiting the immunity of T-cells targeting tumors [92, 93]. Autophagy in CD4 + T cell can be eliminated when they are displayed to lipid, especially elevated level of FAs [94]. Though the autophagy-EV pathway cannot be directly established, and the lipid level of CD4 + T-cells in the TME can be difficult to determine, insights of this novel pathway is still worth exploring.

B-cells

Cancer associated B-cells have been shown to be related to better prognosis in cancer, as exemplified in some breast or ovarian cancer patients [95]. B-cells can undergo metabolic prolife modification characterized by increased lipid uptake for membrane synthesis, which can appear as lipid rafts and be mediated by the increased lipid accumulation in cancer cells [96]. Lipid rafts, which contain cholesterol, and are responsible for adhesion abnormalities, unprosperous phenotypes of transferring, and infiltration in cancer cells, can be characterized as a result of that modulated lipid profile. Lipid rafts in B-cell membranes are crucial for antigen presentation and receptor signaling. The linkage of lipid rafts between B-cells and cancer cells are likely to be associated with enhanced or diminished immunological capability of eliminating cancer cells [96, 97]. Increased production of Stearoyl-CoA Desaturase (SCD), and cancer-related monounsaturated fatty acids (MUFA) has been observed in SV40 cell lines [98]. In cancer cells, SCD facilitates the conversion of saturated FAs into MUFA by SCD via adenosine triphosphate citrate lyase, acetyl-CoA carboxylase and FA synthase [99]. This increase in SCD activity and MUFA production suggests that these components may play a role in enhancing the resistance of cancer cells to apoptosis [98]. Specifically, SCD and MUFAs are involved in the activation of the Wnt/β-catenin pathway [100], which can enhance cancer cell survival and proliferation [101]. However, cell-extrinsic SCD plays a role in the initial development of B cells and the establishment of germinal centers, which is capable of consolidating immunity [102]. Specifically, cholesterol, FAs, and oxysterols, oxidized metabolite from cholesterol, all of which can be modified significantly by the modulated lipid metabolism from cancer cells, have been shown to be able to influence B-cell functionality. Notably, short-chain FAs have been reported to damage or B cell immunity recently [103, 104].

Interestingly, as shown in Fig. 5, Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) -expressing B cells are usually associated with poor prognosis in some cancer types by regulating cancer lipid metabolism. These B-cells are not directly under the modulation of cancer cells but encoded by EBV, especially under the regulation of LMP1 which are prominently expressed on B-cells. However, the LMP1 expressed on these B-cells are capable of regulating cancer cell metabolism. LMP1 is capable of individually initiating de novo lipid synthesis and LD construction, which both greatly regulate nasopharyngeal carcinoma and Hodgkin’s lymphoma cell metabolism, and enhance the expression, development and invigoration of SREBP1, a significant switch for lipogenesis and FASN in EBV-infected nasopharyngeal carcinoma tumor cells. In this process FASN is an important enzyme responsible for de novo biogenesis of FAs in cancer cells. Moreover, LMP1 has also been shown to initiate FASN and enhance the amount of LD construction in an EBV-negative Burkitt’s lymphoma cell line. Notably, in the experiment, interdiction of lipogenesis in EBV-negative Burkitt’s lymphoma cells led to prioritized elimination of LMP1-expressing B cells and greatly impeded the transformation of primary B cells by EBV [105,106,107,108]. This reveals the intricate relationship between LMP1-expressing B cells, FASN, and the prognosis of some EBV-induced cancer, such as nasopharyngeal carcinoma and Hodgkin’s lymphoma and even EBV-negative Burkitt’s lymphoma.

Fig. 5
figure 5

EBV-associated lipid metabolic interaction between B-cells and cancer cells. EBV can invade both B-cells and cancer cells, presented by the existence of LMP1 on these cells’ membrane. In cancer cells invaded by EBV, LMP1 from either cancer cell membrane or B-cell membrane can trigger activated lipid metabolism in cancer cells. When cancer cells are not invaded by EBV, the B-cells invaded by EBV with LMP1 can also trigger increased level of lipid metabolism in cancer cells. The lipid metabolism can be featured by a closed loop between SREBP1, FASN, and LD

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As to the novel autophagy-EV pathway, in hepatocellular carcinoma cells, EVs related to HBV secreted from liver cells invaded by Hepatitis B virus are capable of regulating cell mortality by triggering the chaperonemediated autophagy (CMA) pathway, as in Fig. 6, showing the potential to counteract anti-apoptotic effects in hepatocellular carcinoma cells [109]. Notably, the level of BCL (B-cell lymphoma)-2 in the EVs, and a significant component, lysosomeassociated membrane protein (Lamp2a), are elevated [109]. BCL-2 in this case is a membrane protein that can block apoptosis in B cells [110]. Notably, the triggering of CMA leads to enhanced LD degradation to produce enough free FAs for energetic usage. Moreover, LDs can be stored in cells that lack the expression of Lamp2a [111]. In this case, lipid can be accumulated in liver cancer cells with their anti-apoptotic capability increased, leading to the hypothesis of the modification of lipid milieu which can influence B-cells in the TME. Simultaneously, the EVs containing BCL-2 may directly influence the immunity of B-cells in the TME and affect cancer prognosis.

Fig. 6
figure 6

HBV-associated B-cell cancer cell EV-autophagy pathway. HBV can infect some liver cells, which can release EVs before they are transformed into cancer cells. The bcl-2 and lamp2a in the EVs can strengthen the anti-apoptotic effect of B-cells and increase the level of free FAs in liver cancer cells

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Macrophages

TAMs are a significant component of the TME. The increased FA levels absorbed by gastric cancer cells in the surrounding of TAM can promote TAM lipid accumulation which can increase their lipid level, further inducing even the polarization of a tumor-promoting phenotype (M2 macrophages) and increasing their programmed death ligand 1 (PD-L1) expression, even interfering anti–tumor T cell reactions [93]. Cancer cells can induce the obliteration of some subtypes of macrophages via the construction and transportation of cholesterol supported by the unfolded protein response element known as X-box binding protein 1 (XBP1). In research, inhibiting of XBP1 genetically or pharmacologically, or diminishing the cholesterol level notably can elevate the activity of M1-like macrophages (CD11c + CD206), which often opposes tumor growth. Simultaneously, the content of M2-like macrophage (CD11cCD206+) supporting tumor infiltration remains the same [112]. Stabilin-1, a significant PS (phosphatidylserine) receptor, has been identified as a key role in the immunosuppressive in the function of M2 [113]. The expansion of primitive tumors, was alleviated in rodents with shrunk Stabilin-1 expression particularly in macrophages [113, 114]. This promising prognosis can be due to the modified PS metabolism from tumor cells, which acts on M2 and then in turn has effect on the prognosis of cancer.

Macrophages have also participated in the autophagy-EV pathway, as displayed in Fig. 7. EVs from hypoxic glioma can saliently induce autophagy in macrophages and M2-like macrophage polarization, which subsequently enhanced tumor growth and spread in both in vitro and in vivo settings [115]. Moreover, EVs derived from macrophages have participated in the prognosis of cancer. EVs can carry both mRNA and microRNA, which they deliver to other cells [116]. In the autophagy-EV pathway, EVs from macrophages can transfer miRNA to cancer cells [117]. In specific conditions, miR-4535 from EVs can be transported to targeted metastatic melanoma cells. Once inside these cells, miR-4535 enhances their metastatic spread by muting the autophagy pathway [118].

Fig. 7
figure 7

Macrophage cancer cell EV-autophagy pathway. Macrophages can release EVs into cancer cells releasing miR-4535. Cancer cells can release EVs into macrophages and induce autophagy and M2-like macrophage polarization

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Microvesicles derived from colorectal tumors can induce monocytes to acquire macrophage-like characteristics [119]. These microvesicles notably contain miR-222, known for its tumor-suppressive effects in lung cancer [120]. Additionally, miR-222 transported by these tumor-derived microvesicles can inhibit autophagy in renal cell carcinoma cells [121]. However, a meta-analysis pointed out that upregulated expression of miR-222 is related to poor prognosis in cancer patients [122]. Moreover, overexpression of miR-222-3p has been linked to increased lipid storage [123]. These findings further complicate the case, but what can be confirmed is that microvesicles can participate in the transportation of miR-222 via the autophagy-EV pathway to affect cancer prognosis.

Other

In the TME, the lipid-rich environment in the TME resulting from tumor cells can also influence NK cytotoxicity. Some extrinsic stimulation can affect the lipid profile of NK cells and affect their immunity: Tumor cells can secrete tumor-associated C–C and C–X–C motif chemokines capable of absorbing freshly synthesized myeloid-derived suppressors (MDSCs) to the TME [124, 125]. Under some circumstances, MDSCs synthesized by stimulation of major cancer surgery is capable of initiating an upregulated expression of scavenger receptors on NK cells. Consequentially, the NK cells speed up absorbing lipid, reprogram their lipid metabolism and end up losing their immunity and assisting the elimination of their autologous anti-tumor activity [126, 127]. One research applied FA administration (which may be released by lipolysis in adipocytes near cancer cells), along with the administration of PPARα/δ agonists, to result in the hindrance of mechanistic target of the glycolysis facilitated by the mammalian target of rapamycin (mTOR). This likely imitation of the lipid environment of the TME initiates lipid storage in NK cells promoted by PPAR, leading to entire ‘freeze’ of their metabolic status and mobilization, further hindering mobilization of the transfer of cytotoxic components to the NK cell-tumor interface. In this process, the disruption of PPARα/δ or the blockage of the lipid transportation into mitochondria was able to retract the metabolic ‘freeze’ in NK cells and reinstate their cytotoxic capabilities [44, 128]. Interestingly, both PPARα and PPARδ have been validated to be hoisted in colorectal cancer cells in comparison with dichotomized nearby normal tissues. However, PPARγ, through the inhibition of whose target gene in cancer cells cancer cell progression can be promoted, was suppressed in hepatocellular carcinoma cells [129, 130]. This relationship provides the possibility that cancer cell might be capable of regulating different subtypes of PPAR and FA, which might lead to differentiated results of cancer prognosis in different cancer types by regulating NK immunity.

Neutrophils have been indicated by study to be negatively related to cancer prognosis and play a role in the accumulation of lipid in cancer cells. Tumor-favored neutrophils can be initiated to store lipids internally because of suppression of the ATGL (Adipose Triglyceride Lipase) enzyme triggered by lung mesenchymal cells [131]. Further, lipid-storing neutrophils can transfer lipids in them to cancer cells, modifying the lipidomic profile of cancer cells [132]. Mouse and human polymorphonuclear-MDSCs (polymorphonuclear-MDSCs are dysregulated neutrophils in the TME), which are possibly regulated by cancer cells by secreting tumor-associated C–C and C–X–C motif chemokines, which can attract freshly synthesized MDSCs to the TME, are reported to prominently increase the content of FA transport protein 2 [124, 125, 133]. This finding supports that FA transport protein 2 can suppress the immune responses triggered by neutrophils, indicating that cancer cells may suppress the immunity of neutrophils by upregulating neutrophil FA level.

Conclusions and discussions

The TME is a complex environment that contains cellular and non-cellular components. Cancer cell can influence the lipid milieu of the non-cellular region of the TME, further affect the immune and stromal cells in the TME. These immune and stromal cells can ultimately affect cancer cells, thus influencing cancer prognosis. In this process, phospholipid, FAs, and cholesterol, all of which are upregulated in cancer cells and contribute to the lipid-rich environment of the TME, play key roles in the interaction mediated by lipid. Adipocytes are the key to the lipid-rich environment in the TME, given that they produce lipid into the TME via lipolysis. The rich FA level in the TME can cause immune suppression of T-cells, B-cells, NK cells, and TAMs. Specifically, whether FA can suppress or enhance the immunity of B-cells is still debatable. FA can influence the interaction between Teff and Treg. FA has also differently affected CAFs, TECs, and stellate cells in the TME, leading to poor cancer prognosis. Concurrently, cholesterol accumulation can cause T-cells to be immune-unfavorable, and endothelial cells to be perilous to cancer cells. However, its function in B-cells is still debatable. Phospholipid can be linked to diminished immune capacity in macrophages and interact with stellate cells. The phospholipid level in cancer cells can be increased by cancer cells. Notably, FA, cholesterol, and phospholipid can all improve the cancer-favorable characteristics of CAFs. The autophagy-EV pathway, existing in both cancer cells and stromal/immune cells, can finally affect cancer cells mediated by the lipid in the EVs. This pathway has been revealed between cancer cells and T-cells/B-cells/adipocytes/fibroblasts.

The discoveries of these relationships can lead to insights of the modelling of prognostic prediction using bioinformatic tools: 2 models for breast cancer/ colorectal carcinoma prognostic analysis utilizing genes involved in lipid metabolism have found out prognostic outcome is linked with elevated immunological infiltration, possibly from the TME and the intricate relationship between cancer cells and stromal/immune cells [134, 135]. The discovers of new genes involved in lipid metabolism can also be significant biomarkers for cancer prognosis. With lipidomic analysis being done on the TME, either on cancer cells or immune/stromal cells, more clear prognosis can be achieved: Different hepatocellular carcinoma stages have been monitored by lipidomic means [136]. EVs can be explored bioinformatically for cancer prognosis as well: lipidomic data from plasma EVs were inspected using least absolute shrinkage and selection operator, and random forests, with lipidomic characteristics that can discriminate early and late-stage non-small cell lung cancer successfully identified [137].

With bioinformatical tools identifying novel markers in lipid metabolism, laboratory work can be focused on those biomarkers or lipid metabolites which can participate in the lipid metabolism associated interaction between cancer cells and immune/stromal cells in the TME and influence cancer prognosis. In conclusion, focusing on the lipid metabolism-associated interaction between cancer cells and immune/stromal cells in the TME can provide insights into the more precise prognosis.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

TME:

Tumor Microenvironment

FA:

Fatty Acid

FAO:

Fatty Acid Oxidation

ECM:

Extracellular Matrix

CAF:

Cancer-Associated Fibroblast

SREBP:

Sterol Regulatory Element-Binding Protein

FASN:

Fatty Acid Synthase

ACLY:

ATP Citrate Lyase

FAT:

Fatty Acid Translocase

CD:

Cluster of Differentiation

FABP:

Fatty Acid-Binding Protein

LDL:

Low-Density Lipoprotein

HDL:

High-Density Lipoprotein

IFN:

Interferon

TEC:

Tumor Endothelial Cell

TCR:

T Cell Receptor

LD:

Lipid Droplet

PD-L1:

Programmed Death-Ligand 1

CPT1A:

Carnitine Palmitoyltransferase 1 A

TAM:

Tumor-Associated Macrophage

SCD:

Stearoyl-CoA Desaturase

MUFA:

Monounsaturated Fatty Acid

EBV:

Epstein-Barr Virus

LMP1:

Latent Membrane Protein 1

CMA:

Chaperone-Mediated Autophagy

BCL:

B-cell lymphoma

Lamp2a:

Lysosome-Associated Membrane Protein 2a

MDSC:

Myeloid-Derived Suppressor Cell

NK:

Natural Killer cell

PPAR:

Peroxisome Proliferator-Activated Receptor

XBP1:

X-Box Binding Protein 1

ATGL:

Adipose Triglyceride Lipase

PS:

Phosphatidylserine

cAMP/PKA:

Cyclic Adenosine Monophosphate / Protein Kinase A

PTEN:

Phosphatase and Tensin Homolog

ATM:

Ataxia Telangiectasia Mutated

BNIP:

BCL2/Adenovirus E1B 19 kDa Interacting Protein

LPA:

Lysophosphatidic Acid

VEGF:

Vascular Endothelial Growth Factor

PSC:

Pancreatic Stellate Cell

HSC:

Hepatic Stellate Cell

ET:

Endothelin

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Acknowledgements

We sincerely appreciate the financial assistance provided by the National Natural Science Foundation of China (grant numbers: 32160158, 81460468) and the Natural Science Foundation of Jiangxi Province (grant numbers: 20232BAB206112, 20202BAB206045) for this work. The final manuscript has been read and approved by all authors. Our gratitude also extends to all the participants who contributed to this study.

Funding

The financial assistance is provided by the National Natural Science Foundation of China (grant numbers: 32160158, 81460468) and the Natural Science Foundation of Jiangxi Province (grant numbers: 20232BAB206112, 20202BAB206045) for this work.

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  1. Zhongshu Lin and Guanxiang Hua contributed equally to this work.

Authors and Affiliations

  1. Queen Mary College, Nanchang University, Nanchang, China

    Zhongshu Lin, Guanxiang Hua & Xiaojuan Hu

  2. School of Biological and Behavioural Science, Queen Mary University of London, London, UK

    Zhongshu Lin & Guanxiang Hua

  3. School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China

    Xiaojuan Hu

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Zhongshu Lin prepared all the figures and fully participated in the writing of the whole manuscript. Guanxiang Hua participated in the writing of the whole manuscript. Xiaojuan Hu is mainly responsible for the supervision of the manuscript and organization of ideas for the article. All authors reviewed and approved the manuscript.

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Lin, Z., Hua, G. & Hu, X. Lipid metabolism associated crosstalk: the bidirectional interaction between cancer cells and immune/stromal cells within the tumor microenvironment for prognostic insight. Cancer Cell Int 24, 295 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-024-03481-4

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Cancer Cell International

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