Mutations that drive tumorigenesis cause metabolic alterations (Min and Lee, 2018). The metabolism alteration has been considered an essential hallmark of tumorigenesis (Hanahan and Weinberg, 2011; Pavlova and Thompson, 2016). Lipid metabolism, one of the main sources of energy and basic component for living cells, is reprogrammed to meet the need for energy and nutrient supply to support the rapid growth of tumor cells. In tumor cells, the lipid uptake and synthesis are different from those in normal cells because of the reprogrammed metabolism. For example, tumor cells with RAS mutations can enhance lipid synthesis by upregulating the activity of phosphoenolpyruvate carboxykinase 1 (PCK1) (Xu et al., 2020). Cholesterol is an essential lipid of the cell membrane and a basic component for cancer cell proliferation. Cholesterol is also involved in intratumoral steroidogenesis and vitamin D synthesis, and serves as a signal molecule (e.g., estrogen-related receptor Alpha (ERRα) ligand) (Chimento et al., 2018). Cholesterol metabolism reprogramming in cancer changes the availability and usability of intratumoral cholesterol, and the cholesterol-derived metabolites contribute to cancer progression and immunosuppression (Huang et al., 2020). Lipid metabolism alteration occurs in both cancer cells and nonmalignant cells (e.g., stromal cells and immune cells) in the tumor microenvironment (TME). In the TME, the matrix compounds can provide raw materials for tumor cells to quickly synthesize the necessary molecules. It has been reported that under the conditions of local hypoxia and lipid depletion, acetate can serve as an alternative source for lipid synthesis in cancer cells (Comerford et al., 2014). Moreover, tumor-associated stromal cells can also provide nutrients for tumor development. For instance, tumor-associated fibroblasts could transport lipids to adjacent cancer cells through cargo vesicles for maintaining their fast proliferation (Santi et al., 2015).

Immunotherapy, representing a breakthrough in the cancer field, has been widely applied in the treatment of various cancers, including metastasis and advanced cancers, by activating or normalizing the immune system. However, immune evasion typically leads to poor anti-tumor effects of immunotherapy (Beatty and Gladney, 2015). Lipid metabolism alteration not only plays an important role in cancer cell proliferation and migration but also affects the recruitment and function of immune cells. Lipid metabolism abnormality in the TME is an important mechanism leading to immune evasion. For example, lipid accumulation in myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), tumor-associated macrophages (TAMs), and CD8⁺ T cells have been demonstrated to skew these immune cells towards immunosuppressive and immune-escaping phenotypes in the TME (Herber et al., 2010; Al-Khami et al., 2017; Ma et al., 2019; Rabold et al., 2020; Su et al., 2020). Therefore, targeting lipid metabolism is a potential strategy for tumor immunotherapy, which has been reviewed by Bian, et al. (2021); Broadfield, et al. (2021).

However, it remains a challenge to achieve precise regulation of intratumor lipid metabolism because of the complexity and heterogeneity of the TME. Furthermore, the lipid metabolism alteration in various tumors is different because of various genetic backgrounds and tissue origins, which has been described in a review (Bi et al., 2018). The fast-cycling tumor cells rely on aerobic glycolysis for energy supply, while the slow-proliferation cancer cells under glucose-deprived conditions use lipid oxidation as the main metabolism pattern (Hoang-Minh et al., 2018). Nanotechnology, which is emerging as a promising therapeutic tool for targeting some specific tissues or cells, has been actively explored for application in anticancer immunity enhancement via regulating metabolism, e.g., glycolysis (Wang et al., 2019; Chen et al., 2020) and lipids (Jin et al., 2019; Kim D. et al., 2021). Therefore, nanotechnology-based targeting delivery may provide a potential method for cell-targeting regulation of lipid metabolism in the TME for improving immunotherapy. Herein, we will summarize nanotechnology-based therapeutic strategies for reprogramming lipid metabolism and enhancing tumor immunotherapy.

The TME is characterized by hypoxia and glucose deprivation. To overcome the nutrient-deficient environment, the tumor cells develop survival mechanisms via metabolic reprogramming. Different from glycolysis, the diversity of structure and characteristics of lipid species may lead to the complexity of lipid metabolism in cells. It was found that the commonly changed lipid metabolism and corresponding pathways in tumors included fatty acids metabolism, cholesterol metabolism, and arachidonic acid metabolism, and PPAR (peroxisome proliferator-activated receptor) signaling by the analysis of various omics data (Hao et al., 2019). Meanwhile, these changes also play an important role in coordinating the immune cells toward an immunosuppressive phenotype.

PPARs serve as lipid sensors in response to the increased energy requirement and are fatty acid-activated transcription factors, belonging to the nuclear hormone receptor superfamily with three nuclear receptor isoforms, PPARα, PPARβ/δ, and PPARγ ( Figure 1A) (Peng et al., 2021). Lipid-derived metabolites serve as the natural ligands of PPARs. The tissue distribution of PPAR subtypes and their endogenous ligands and target genes are summarized in a review by Monroy-Ramirez, et al. (Monroy-Ramirez et al., 2021). PPARα is a regulator of fatty acid metabolism and involved in substrate transport, substrate oxidation, and oxidative phosphorylation (OXPHOS); PPARδ plays a vital role in fatty acid oxidation and blood glucose regulation; PPARγ can facilitate energy storage by promoting adipogenesis and lipid synthesis in different cell and play a major role in adipocyte differentiation (Christofides et al., 2021). The reprogrammed lipid metabolism and the resultant metabolites could affect tumor immunity via the PPAR signaling. For example, PPARδ signaling increased the contents of neutral lipid and membrane cholesterol in malignant B cells, and caused STAT3 activation and weakened immunostimulatory interferons (IFNs) signaling responses; therefore, PPARδ inhibition could promote the antitumor immune activity of IFNs (Sun et al., 2018).

Both fatty acids and cholesterol are de novo synthesized from acetyl CoA from the tricarboxylic acid cycle (TCA) (as illustrated in Figure 1B, Wang et al., 2020). Fatty acid metabolism mainly includes de novo synthesis, oxidation, desaturation, and extension of fatty acids. Tumor cells are characterized by abnormal energy metabolism and up-regulated endogenous fatty acid synthesis (Rohrig and Schulze, 2016). Exogenous intake and de novo synthesis of fatty acids could be increased to meet the insistent need of tumor cells to produce plasma membrane phospholipids and lipid-based signaling molecules. Meanwhile, fatty acid metabolism is also changed in the intratumoral immune cells. For instance, an increased rate of fatty acid synthesis was found in the tumor-infiltrating Tregs, which could contribute to the Treg expansion in the TME (Pacella et al., 2018). Natural killer (NK) cells with the upregulated PPARα-mediated fatty acid catabolism showed impaired antitumor function (Michelet et al., 2018). In addition, it was found that the fatty acid oxidation (FAO) in the RIPK3-deficient TAMs could increase because the RIPK3-mediated ROS–caspase 1 suppression resulted in the activated PPARα/γ pathway, thus leading to TAM accumulation and M2 differentiation in TME during hepatocarcinogenesis (Wu et al., 2020). However, in breast cancer, the truncated PPARγ caused by capspace-1 mediated cleavage could attenuate MCAD activity and inhibit FAO; as a result, the consequent lipid droplet accumulation in TAM promoted the differentiation of TAMs to a pro-tumor phenotype (Niu et al., 2017). It indicated either activated PPARγ or truncated PPARγ could promote the pro-tumor effect of TAMs, but the further investigation should be carried out.

Cholesterol homeostasis is important to maintain the normal functions of the cell membrane and is regulated by de novo synthesis, import, and efflux [as illustrated in Figure 1B (Wang et al., 2020)]. Cholesterol level is typically enhanced in tumor tissues/cells, in which cholesterol synthesis may be up-regulated through PI3K/AKT/mTOR signaling or TP53 [see the review of (Kuzu et al., 2016)]. A study revealed that there was about 3-fold higher cholesterol level in tumor tissue compared to the normal (10.7 vs. 3.6 μmol/g) (Yoshioka et al., 2000). Cholesterol is involved in tumor-associated-macrophage polarization. The increase of cholesterol efflux from macrophages in the TME can activate the IL-4 signaling pathway and downregulate the IFN-γ transcription, thus inducing macrophages to a tumor-promoting immunosuppressive phenotype (Goossens et al., 2019). After homing to the tumors with rich cholesterol, T cells are prone to be exhausted due to increased cholesterol uptake and accumulation (Ma et al., 2019). Meanwhile, the impaired synthesis of cholesterol can diminish the anticancer ability of intratumoral invariant natural killer T (iNKT) cells; for example, the overproduced lactic acid in the TME can cause insufficient cholesterol synthesis in the iNKT cells by suppressing PPARγ expression, and thereby reduced IFN-γ production (Fu et al., 2020). Besides, cholesterol derivatives, e.g., oxysterols, also play a certain role in regulating the tumor immune microenvironment. Oxysterol is the oxidized form of cholesterol and shows significant enrichment in the TME (Kloudova et al., 2017). The enriched oxysterol in the TME can not only increase the recruitment of neutrophil (Raccosta et al., 2013) and MDSC (Baek et al., 2017) but also downregulate the antigen-presenting function of DCs (Villablanca et al., 2010) and the effector function of CD8⁺ T cells (Baek et al., 2017), resulting in the tumor immune evasion. In addition, macrophages may also be regulated by oxysterols to promote tumor cell metastasis (Eibinger et al., 2013).

Prostaglandin E2 (PGE2) is produced by arachidonic acid metabolism and is synthesized by cyclooxygenase (COX) and prostaglandin synthase [as illustrated in Figure 1C (Li et al., 2017)]. PGE2 is transported to the extracellular space through specific prostaglandin transporters or multidrug resistance-associated proteins (MRP) (Elwakeel et al., 2019). Extracellular prostaglandins activate four specific G protein-coupled receptors (GPCR), EP 1–4, for regulating the physiological activity of cells. COX is overexpressed in many tumors and is associated with immunosuppression accompanied by the high production of PGE2 in the TME (Zelenay et al., 2015). PGE2 overexpression in the TME can promote TAM to differentiate into a pro-tumor subtype and enhance the immunosuppressive functions of MDSCs (Obermajer et al., 2012; Larsson et al., 2015). Furthermore, the excessive production of PGE2 in the TME promotes the development and differentiation of Treg cells (Sharma et al., 2005). At the same time, the abundant PGE2 in the TME impairs the function of DC and NK cells, and abrogates the activation of CD8⁺ T cells, contributing to the tumor immune evasion (Ahmadi et al., 2008; Bottcher et al., 2018).

Alterations of lipid metabolism in the TME play a significant role in the formation of tumor immunosuppressive microenvironment and lead to tumor immune evasion. To enhance tumor immunity via regulating lipid metabolism in the TME is a very promising direction for cancer treatment. However, it is difficult for precise regulation of lipid metabolism in the TME because of the obstacles against efficient drug delivery in the complex and heterogenetic TME to reach the target cells. Nanotechnology has recently drawn great attention for its application for remodeling TME (Fernandes et al., 2018; Sun et al., 2020). Nanotechnology-based drug delivery can significantly prolong the drug circulation time and improve bioavailability. It is an attractive strategy to effectively regulate lipid metabolism in the TME to enhance tumor immunity.

Notably, the nanomaterials could affect the lipid metabolism and functions of cells (Kim S. J. et al., 2021; Florance et al., 2021). Therefore, the biological effects of nanoparticles should be further studied, and this part will not be discussed in the review.

Immunotherapy represents a new era for cancer treatment and can be combined with chemotherapy, radiotherapy, and surgery. Off-target effects cause a lower-than-expected rate of the primary outcome of immunotherapy. The TME is a dynamic network; the cell population and phenotype are affected by the metabolic switch. There is a lipid-rich environment in many solid tumors, and lipid metabolism is conducive to tumor cell growth and immune response (Cruz et al., 2020). Because of the plasticity of immune cells, they can be directed toward an antitumor phenotype by regulating the metabolic checkpoints. The targeting lipid metabolism via nanotechnology provides a potential strategy to improve cancer therapy by regulating immune-metabolic signals. Although nanomedicines have been explored for tumor metabolism regulation (e.g., glycolysis and iron metabolism) (Wang et al., 2019; Lin et al., 2021), it is still an infant field of applying nanotechnology for lipid metabolism regulation for immunotherapy.

Lipid metabolism is highly diverse and complex due to the vast variety of endogenous lipid molecules and metabolites. The advance of understanding the regulatory pathways and the biological functions of the lipid molecules in different cells in TME will promote the further application of nanomedicine in regulation of lipid metabolism and immunity. For example, cholesterol may play a dual role in CD8⁺ T cells, and it either promotes anti-tumor responses or induces CD8⁺ T cell exhaustion (Yang et al., 2016; Ma et al., 2019). Therefore, how to fine-tune cholesterol hemostasis could be essential for precisely directing immune responses. For this purpose, nanotechnology-based drug delivery can provide a useful tool for elegant control of drug fate and action.

Nanotechnology can protect the encapsulated drugs from degradation and clearance, and thus prolong the drug half-life, as well as improve the solubility of drugs. Various immune cells in the TME play different roles in tumor immunity (Hao et al., 2021), and therefore, the targeting delivery to a specific group of immune cells is a prerequisite for precise regulation of the tumor immune microenvironment. Via surface modification with a targeting ligand that can specific binding to a certain receptor of the immune cells, the nanoparticles can selectively deliver drugs to the targeted cell type in the TME. It is a goal to achieve targeted delivery to a specific cell population (e.g., TAMs), and even a specific phenotype of a cell group (e.g., M2-like TAMs) in the TME. With the advance of nanotechnology-based delivery, precise regulation of lipid metabolism (e.g., targeting cholesterol metabolism in a specific cell type) will be feasibility, though there are still many unknowns to be explored, for example, to illustrate the relation between the drug biofate and the nanoparticle properties such as shape, charge, material, and surface functionalization.