Human mortality is becoming increasingly dominated by cancer, which has long posed a significant public health concern [1]. According to the latest estimates by the World Health Organization (WHO)’s International Agency for Research on Cancer (IARC), the number of new cancer cases reported worldwide have risen to 19.29 million, with 9.96 million deaths reported by the year of 2020 [2]. For decades, scientists have been seeking effective cancer therapeutic targets and developing innovative cancer treatment strategies to defeat cancer. Over the past few decades, combining nanotechnology, materials science, and biotechnology has accelerated the development of the innovative nanomedicine field for cancer treatment [3]. Due to the unique appeal of nanomaterials for drug delivery, cancer diagnosis and imaging, and immune vaccine development, interest in applying nanotechnology to cancer treatment has grown, and a considerable level of technical success has been achieved ^[4][5][4,5]. Notable examples include small superparamagnetic iron oxide nanoparticles, which have been widely used as magnetic resonance imaging (MRI) contrast agents, and the successful introduction of the lipid nanoparticle COVID-19 mRNA vaccine ^[6][7][6,7]. Lipidic nanomaterials are nanoparticles consisting of lipid-like substances, with their diameters typically being between 10–200 nm [8]. As one of the most popular platforms for cancer treatment, they have demonstrated tremendous therapeutic potential across a wide range of treatment modalities. The natural origin of lipids ensures an ultra-high biocompatibility and degradability, making them superior to other materials like polymers due to their low probability of causing lipid-induced toxicity [8]. Moreover, they also exhibit attractive multifunctional properties, including an encapsulation capability for either hydrophilic or hydrophobic therapeutics, as well as surface properties, such as charge and targeting ligand modifications, that can be easily modified by altering the lipid composition or by attaching antibodies ^[9][10][9,10]. This flexibility allows for precise drug delivery and targeted therapy, making lipidic nanomaterials promising candidates for innovative cancer therapeutic strategies.

The emergence of lipidomic and lipid quantification in recent years has provided large-scale qualitative and quantitative studies of lipid compounds in organisms, providing insights into the functions and changes of lipid compounds under physiopathological conditions, and has also significantly contributed to the development of lipidic nanomaterials ^[11][12][13][11,12,13]. There is growing evidence in that when SM levels are expressed abnormally, it increases the cancer risk ^[14][15][14,15]. Among them, biological studies on the metabolism and function of sphingomyelin (SM) have revealed that effector molecules in the SM metabolic pathway contribute significantly to cell signaling, especially in regulating tumor cell growth, differentiation, senescence, and survival ^[16][17][18][16,17,18]. SM is integral for the membrane, and is an essential structural molecule in the cell membrane. Related enzymes, such as sphingomyelinase (SMase) and sphingomyelin synthase (SMS), strongly regulate its abundance [19]. A critical role for SM content and metabolic enzyme activity in signaling pathway transduction and therapy must be considered. Furthermore, SM metabolites have diverse biological functions across various cancerous processes [20]. For example, ceramide (Cer), produced by the SMase-mediated hydrolysis of SM, is closely associated with cell death, senescence, and cellular arrest ^[21][22][21,22]. Upon further metabolism, Cer can be converted to a pro-survival metabolite called sphingosine-1-phosphate (S1P), which is an anti-apoptotic molecule ^[23][24][23,24]. Thus, the dynamic transformation processes associated with SM metabolism are critical for mediating the fate of cancer cells.

Currently, an increasing number of investigators are focusing on the design of lipidic nanomaterials based on SM metabolism, initiating preclinical trials for different types of tumors to evaluate the potential application of therapeutic strategies utilizing SM, Cer, and S1P ^[25][26][25,26].

2. Synthesis and Metabolism of SM

2.1. Structure and Distribution of SM

In the 1880s, Johann Ludwig Wilhelm Thudichum [27] discovered and named the first sphingolipid SM, which is a phospholipid that is mainly found in vertebrates, accounting for 2% to 15% of total phospholipids, respectively [27]. Each molecule of SM is composed of a sphingosine (Sph) molecule, a fatty acid, and phosphorylcholine polar head group, and is characterized by a hydrophilic head and a hydrophobic tail made of two fatty acid chains, allowing them to form a lipid bilayer, the chemical structure of which is shown in Figure 1 (top left) ^[28][29][28,29]. The hydrophobic tail of SM is typically 16 to 24 carbons in length. At the same time, the sphingoid backbone can be either dihydrosphingosine, sphingosine, or 4-hydroxysphinganine, thus conferring heterogeneity to the SM molecule [30]. Various studies have shown that SM is present in most intracellular compartments, including the Golgi apparatus (which produces most of the SM molecules) and the plasma membrane (PM) (Figure 2) [16]. SM is also highly enriched in the outer leaflet of the PM and is the major component of the PM [31]. Exceptionally, erythrocytes and neural tissue have a higher SM content [20]. It has been estimated that the proportion of SM in the PM of fibroblasts can account for 40% to 90% of the total SM in the cell, respectively [32].

2.2. SM Synthesis

SM is synthesized by two major isoforms of SMS, SMS1 (located in the trans-Golgi) and SMS2 (located in the trans-Golgi and PM) [33]. SMS2 in the PM is the only enzyme capable of synthesizing SM, and may have the unique function of directly maintaining SM content in the PM. It is unknown where the primary site of SM synthesis is located, but it occurs either on the luminal side of the trans-Golgi or in the extracellular leaflet of the PM (orange arrow in Figure 2) ^[34][35][34,35]. Cer is the substrate for this reaction, and this molecule is synthesized in the endoplasmic reticulum (ER). Thus, Cer must be transferred from its site of synthesis to the Golgi via a mediator termed the ceramide transfer protein (CERT) (a non-vesicular mechanism). The transfer of a phosphocholine headgroup from phosphatidylcholine to Cer to generate SM is catalyzed by SMS1, along with the generation of diacylglycerol (DAG) [36]. CERT is a cytoplasmic protein with two unique domains: the START (StAR-related lipid-transfer) domain for Cer recognition and the PH (pleckstrin homology) domain for phosphatidylinositol binding ^[36][37][36,37]. Unlike SMS1, SMS2 is not reliant on CERT-mediated Cer molecules to synthesize SM due to its unique cellular location, and is the only type of SMS present in the PM. Its most prominent mechanism is likely in converting local Cer to SM [38]. Sphingomyelin synthase-related protein (SMSr) is an enzyme present in the ER that is capable of converting Cer to ceramide phosphorylethanolamine (CPE), followed by the head group being exchanged or methylated to produce SM (green arrow in Figure 2) ^[31][39][31,39]. As CPE synthesizes extremely slowly, SM is produced in much lower amounts than when SM is synthesized in the Golgi, and it is commonly believed that SMSr regulates the balance of Cer in the ER to prevent excessive accumulation of Cer.

2.3. SM Metabolism

The metabolites of SM include Cer, Sph, and S1P, which are an essential class of biologically active signaling molecules [40]. Cer and Sph are important components of the stress response regulatory system, mediating cell cycle arrest and inducing apoptosis. However, S1P exhibits the opposite effect, promoting cell growth, invasion, and survival [41]. The synthesis and catabolism of these metabolites constitute a dynamic equilibrium relationship that judges the cell fates (e.g., cell proliferation, differentiation, or apoptosis). The regulation of these interconnected cell fates results from interactions and mutual equilibria between regulatory molecules within the cell. This subtle relationship between Cer, Sph, and S1P has been described as a “sphingomyelin rheostat” ^[21][22][21,22].

3. Role of SM in the Development of Tumors

Active molecules of the SM-related pathways play a crucial role in tumorigenesis and progression, and alterations in their related signaling play a vital role in the induction of cancer cell death or survival (Table 1).