The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy.

Cancer, a disease that modern medicine has not fully understood and conquered, with its high incidence and mortality, deprives countless patients of health and even life. According to global cancer statistics, there were an estimated 19.3 million new cancer cases and nearly 10 million cancer deaths in 2020, with the age-standardized incidence and mortality rates of 201.0 and 100.7 per 100,000, respectively. Although remarkable advancements have been made in therapeutic strategies recently, the overall prognosis of cancer patients remains not optimistic. Consequently, there are still many severe challenges to be faced and difficult problems to be solved in cancer therapy today. Epigallocatechin gallate (EGCG), a natural polyphenol extracted from tea leaves, has received much attention for its antitumor effects. Accumulating investigations have confirmed that EGCG can inhibit tumorigenesis and progression by triggering apoptosis, suppressing proliferation, invasion, and migration, altering tumor epigenetic modification, and overcoming chemotherapy resistance. Nevertheless, its regulatory roles and biomolecular mechanisms in the immune microenvironment, metabolic microenvironment, and immunotherapy remain obscure. In this article, we summarized the most recent updates about the effects of EGCG on tumor microenvironment (TME), metabolic reprogramming, and anti-cancer immunotherapy. The results demonstrated EGCG can promote the anti-cancer immune response of cytotoxic lymphocytes and dendritic cells (DCs), attenuate the immunosuppression of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and inhibit the tumor-promoting functions of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and various stromal cells including cancer-associated fibroblasts (CAFs), endothelial cells (ECs), stellate cells, and mesenchymal stem/stromal cells (MSCs). Additionally, EGCG can suppress multiple metabolic reprogramming pathways, including glucose uptake, aerobic glycolysis, glutamine metabolism, fatty acid anabolism, and nucleotide synthesis. Finally, EGCG, as an immunomodulator and immune checkpoint blockade, can enhance immunotherapeutic efficacy and may be a promising candidate for antitumor immunotherapy. In conclusion, EGCG plays versatile regulatory roles in TME and metabolic reprogramming, which provides novel insights and combined therapeutic strategies for cancer immunotherapy.

Li D ，Cao D ，Sun Y ，Cui Y ，Zhang Y ，Jiang J ，Cao X ... -  《Frontiers in Immunology》

Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy.

Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.

Nicolini A ，Ferrari P 《Frontiers in Immunology》

Engineered exosome-like nanovesicles suppress tumor growth by reprogramming tumor microenvironment and promoting tumor ferroptosis.

Tumor vaccines that induce effective and sustained antitumor immunity are highly promising for cancer therapy. However, the antitumor potential of these vaccines is weakened due to the immunosuppressive characteristics of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells within the TME; they play an important role in tumor growth, metastasis, immunosuppression, and drug resistance. Fibroblast activation protein-α (FAP) is overexpressed in CAFs in more than 90% of human tumor tissues. Further, FAP+CAFs are an ideal interstitial target for the immunotherapy of solid tumors. Exosomes derived from tumor cells contain many tumor antigens, which can be used as the basis of tumor vaccines that elicit strong antitumor immunity. Almost all exosome-based cancer vaccines have been designed and developed for tumor parenchymal cells. Moreover, the exosome production is very low and the purification is very difficult, limiting their clinical application as tumor vaccines. In this study, we developed FAP gene-engineered tumor cell-derived exosome-like nanovesicles (eNVs-FAP) as a tumor vaccine that can be prepared easily and in large quantities. The eNVs-FAP vaccine inhibited tumor growth by inducing strong and specific cytotoxic T lymphocyte (CTL) immune responses against tumor cells and FAP+CAFs and reprogramming the immunosuppressive TME in the colon, melanoma, lung, and breast cancer models. Moreover, eNVs-FAP vaccine-activated cellular immune responses could promote tumor ferroptosis by releasing interferon-gamma (IFN-γ) from CTLs and depleting FAP+CAFs. Thus, eNVs-FAP is a candidate tumor vaccine targeting both the tumor parenchyma and the stroma. STATEMENT OF SIGNIFICANCE: Nanovaccines can activate immune cells and promote an antitumor immune response. In this study, we developed the fibroblast activation protein-α (FAP) gene-engineered tumor cell-derived exosome-like vesicle vaccines (eNVs-FAP). A large number of eNVs-FAP were obtained by continuously squeezing FAP gene-engineered tumor cells. eNVs-FAP showed excellent antitumor effects in a variety of tumor-bearing mouse models. The mechanistic analysis showed that eNVs-FAP promoted the maturation of dendritic cells (DCs), increased the infiltration of effector T cells into target tumor cells and FAP-positive cancer-associated fibroblasts (FAP+CAFs), and reduced the proportion of immunosuppressive cells, including M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), in the tumor microenvironment (TME). Moreover, the clearance of FAP+CAFs helped enhance interferon-gamma-induced tumor cell ferroptosis.

Hu S ，Ma J ，Su C ，Chen Y ，Shu Y ，Qi Z ，Zhang B ，Shi G ，Zhang Y ，Zhang Y ，Huang A ，Kuang Y ，Cheng P ... -  《-》

Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment.

It is notorious that cancer cells alter their metabolism to adjust to harsh environments of hypoxia and nutritional starvation. Metabolic reprogramming most often occurs in the tumor microenvironment (TME). TME is defined as the cellular environment in which the tumor resides. This includes surrounding blood vessels, fibroblasts, immune cells, signaling molecules and the extracellular matrix (ECM). It is increasingly recognized that cancer cells, fibroblasts and immune cells within TME can regulate tumor progression through metabolic reprogramming. As the most significant proportion of cells among all the stromal cells that constitute TME, cancer-associated fibroblasts (CAFs) are closely associated with tumorigenesis and progression. Multitudinous studies have shown that CAFs participate in and promote tumor metabolic reprogramming and exert regulatory effects via the dysregulation of metabolic pathways. Previous studies have demonstrated that curbing the substance exchange between CAFs and tumor cells can dramatically restrain tumor growth. Emerging studies suggest that CAFs within the TME have emerged as important determinants of metabolic reprogramming. Metabolic reprogramming also occurs in the metabolic pattern of immune cells. In the meanwhile, immune cell phenotype and functions are metabolically regulated. Notably, immune cell functions influenced by metabolic programs may ultimately lead to alterations in tumor immunity. Despite the fact that multiple previous researches have been devoted to studying the interplays between different cells in the tumor microenvironment, the complicated relationship between CAFs and immune cells and implications of metabolic reprogramming remains unknown and requires further investigation. In this review, we discuss our current comprehension of metabolic reprogramming of CAFs and immune cells (mainly glucose, amino acid, and lipid metabolism) and crosstalk between them that induces immune responses, and we also highlight their contributions to tumorigenesis and progression. Furthermore, we underscore potential therapeutic opportunities arising from metabolism dysregulation and metabolic crosstalk, focusing on strategies targeting CAFs and immune cell metabolic crosstalk in cancer immunotherapy.

Zhu Y ，Li X ，Wang L ，Hong X ，Yang J ... -  《Frontiers in Endocrinology》

Choline metabolism reprogramming mediates an immunosuppressive microenvironment in non-small cell lung cancer (NSCLC) by promoting tumor-associated macrophage functional polarization and endothelial cell proliferation.

Lung cancer is a prevalent malignancy globally, and immunotherapy has revolutionized its treatment. However, resistance to immunotherapy remains a challenge. Abnormal cholinesterase (ChE) activity and choline metabolism are associated with tumor oncogenesis, progression, and poor prognosis in multiple cancers. Yet, the precise mechanism underlying the relationship between ChE, choline metabolism and tumor immune microenvironment in lung cancer, and the response and resistance of immunotherapy still unclear. Firstly, 277 advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy in Sun Yat-sen University Cancer Center were enrolled in the study. Pretreatment and the alteration of ChE after 2 courses of immunotherapy and survival outcomes were collected. Kaplan-Meier survival and cox regression analysis were performed, and nomogram was conducted to identify the prognostic and predicted values. Secondly, choline metabolism-related genes were screened using Cox regression, and a prognostic model was constructed. Functional enrichment analysis and immune microenvironment analysis were also conducted. Lastly, to gain further insights into potential mechanisms, single-cell analysis was performed. Firstly, baseline high level ChE and the elevation of ChE after immunotherapy were significantly associated with better survival outcomes for advanced NSCLC. Constructed nomogram based on the significant variables from the multivariate Cox analysis performed well in discrimination and calibration. Secondly, 4 choline metabolism-related genes (MTHFD1, PDGFB, PIK3R3, CHKB) were screened and developed a risk signature that was found to be related to a poorer prognosis. Further analysis revealed that the choline metabolism-related genes signature was associated with immunosuppressive tumor microenvironment, immune escape and metabolic reprogramming. scRNA-seq showed that MTHFD1 was specifically distributed in tumor-associated macrophages (TAMs), mediating the differentiation and immunosuppressive functions of macrophages, which may potentially impact endothelial cell proliferation and tumor angiogenesis. Our study highlights the discovery of ChE as a prognostic marker in advanced NSCLC, suggesting its potential for identifying patients who may benefit from immunotherapy. Additionally, we developed a prognostic signature based on choline metabolism-related genes, revealing the correlation with the immunosuppressive microenvironment and uncovering the role of MTHFD1 in macrophage differentiation and endothelial cell proliferation, providing insights into the intricate workings of choline metabolism in NSCLC pathogenesis.

Xiao B ，Li G ，Gulizeba H ，Liu H ，Sima X ，Zhou T ，Huang Y ... -  《Journal of Translational Medicine》