Tumor cells usually have a high demand and affinity for glucose (Bhattacharya et al., 2016). Based on the fact that mannose and glucose are introduced into cells by the same transporters (Thorens and Mueckler, 2010), Gonzalez et al. have proposed that mannose may interfere with glucose uptake by tumor cells, and made relevant experimental verification (Gonzalez et al., 2018). Interestingly, the results showed that mannose treatment did not reduce or even increase the intracellular glucose level, but affected cell growth by interfering with glucose metabolism (Gonzalez et al., 2018). The mechanism at hand is that mannose accumulates in the form of mannose-6-phosphate and the accumulation of M6P suppresses glucose phosphate isomerase (GPI) and other enzymes related to glucose metabolism, which impairs the further metabolism of glucose in glycolysis, tricarboxylic acid cycle, pentose phosphate pathway, and glycan synthesis (Gonzalez et al., 2018). In follow-up experiments, they came up with two important results: First, among various hexoses, only mannose-combined with conventional chemotherapy such as cisplatin and adriamycin can down-regulate Mcl-1 and Bcl-XL protein levels and enhance apoptosis; Second, the inhibitory effect of mannose was negatively correlated with the expression level of mannose phosphate isomerase (PMI) encoded by MPI gene (Figure 1). Therefore, cells with low PMI levels are sensitive to mannose, while cells with high levels are resistant. These results could open up a novel way to fight cancer and provide a safe, simple, potential treatment strategy effectively against many types of cancer by enhancing chemotherapy. However, in terms of the effective dose of mannose, we expect scientists to calculate an appropriate dosage that has maximum effectiveness without any significant side effect. Based on the above mechanisms, a recent study has shown that mannose inhibits cell proliferation and enhances radiation-induced apoptosis in human esophageal squamous carcinoma cells with low MPI expression in a dose-dependent manner (Luo et al., 2022). This suggests that mannose can act as a radiation sensitizer in patients with esophageal squamous cell carcinoma with low MPI expression. There is also a study showed that in the early and middle stages of the development of glioblastoma multiforme (GBM), mannose can be combined with temozolomide concurrent radiotherapy (RT/TMZ) to achieve cure (Liu et al., 2020).

For thyroid cancer, one recent study has found that whether the cell line is sensitive to mannose depends mainly on the enzyme activity of PMI (Ma et al., 2021). Structurally, zinc ions (Zn²⁺) are critical for the binding of the PMI and substrate, so the enzymatic function of PMI depends on Zn²⁺ concentration (Bangera et al., 2019). ZIP10 is a Zn²⁺ transporter expressed during early B cell development that transports Zn²⁺ from outside the cell to the cytoplasm, thereby altering the concentration of Zn²⁺ within the cell (Miyai et al., 2014). The latest study found that in thyroid cancer cells that are not sensitive to mannose, knocking down ZIP10 can significantly improve their sensitivity to mannose, and M6P accumulation in turn enhances the inhibitory effect of mannose on cellular glycolysis (Ma et al., 2021) (Figure 1). These findings suggest that mannose has potential application value in the treatment of thyroid cancer.

In non-small cell carcinoma (NSCLC), it has been proved that mannose has a significant inhibitory effect on the proliferation, invasion, and metastasis of A549 cells. Mannose was shown to be able to induce G0/G1 arrest by down-regulating the expression of PCNA and up-regulating the expression of p21, both of which are related to the concentration of mannose (Wang et al., 2020). Moreover, mannose can promote the expression of phosphorylated GSK-3β, suppress the activation of ERK, and thereby reduce the expression of β-catenin and SNAIL, which in turn reduce N-cadherin and increases E-cadherin, thereby suppressing tumor metastasis (Wang et al., 2020; Luo et al., 2020) (Figure 2). In terms of mechanism, epithelial-mesenchymal transition (EMT) plays an indispensable role in cancer metastasis (Heerboth et al., 2015). Several transcription factors are upregulated in EMT metastatic cells, represented by SNAIL. SNAIL can be combined with the E-cadherin promoter to suppress the expression of E-cadherin and promote EMT (Al Khatib et al., 2019). Phosphorylation of GSK-3β and phosphorylation and destabilization of β-catenin have significant effects on EMT (Geng et al., 2017; Tian et al., 2020). The activation of ERK promotes the phosphorylation level of β-catenin Tyr654, and the phosphorylation of tyrosine 654 at β-catenin promotes nuclear translocation, which in turn promotes the expression of β-catenin in the nucleus. The phosphorylation of GSK-3β can suppress the function of β-catenin and promote the degradation of β-catenin. Mannose significantly reduces the phosphorylation level of tyrosine 654 at β-catenin in cells in vitro by reducing the phosphorylation level of ERK, and promotes the expression of phosphorylated-GSK-3β (Luo et al., 2020). Wang et al. also found that mannose could exert anticancer effects on A549 and H1299 cells by suppressing PI3K/AKT and ERK signaling pathways (Wang et al., 2020). This implies that mannose can be combined with AKT or ERK targeted therapy to treat lung cancer, but further experiments are needed to explore the molecular mechanism of mannose’s anti-cancer effect. It is worth noting that the suppressed migration induced by mannose is more effective on the migration of carboplatin-treated A549 cells. The last point is that mannose significantly enhances the effect of apoptosis after carboplatin treatment (Sha et al., 2020; Wang et al., 2020). All these findings suggest that mannose may be a selective cancer treatment. However, some problems remain, such as in chronic myeloid leukemia (CML), although D-mannose treatment can inhibit K562 cell growth in vitro, it does not reduce the tumor volume in vivo, and ponatinib and D-mannose treatment show severe drug toxicity in mice (Okabe et al., 2021). This reminds us that some approaches require more evaluation when it comes to targeted therapy for glucose metabolism.

\Some peptides act as regulators of innate immunity, activating macrophages and monocytes, thereby releasing chemicals with potential tumor-killing effects (Kager et al., 2010). As an excellent carrier of peptide drugs, liposomes can protect the structure and biological activity of drugs (Kumar Giri et al., 2016). Tumor epitope peptides can be recognized by dendritic cells (DCs) and processed into MHC-I complexes to specifically activate CD8⁺ T cells into cytotoxic T cells (CTLs) to achieve targeted killing effects (Wculek et al., 2020). The mannose receptor (MR) is a member of the C-type lectin superfamily, which is mainly present on the membrane surface of macrophages and DC cells, and plays an important role in antigen presentation (Martinez-Pomares, 2012). Therefore, recently, a relevant research team has developed a mannose modified liposome-epitope peptide drug delivery system, in which mannose improves the bonding rate of liposomes and DC cells, improves the targeting efficiency of epitope peptide liposomes to DC cells, and significantly inhibits the hematogenic spread of lung metastasis of triple negative breast cancer (TNBC) in animal experiments, and has good biosecurity (Yu et al., 2021). In addition, a research team has developed a doxorubicin (DOX)-based mannose nanogel (DM NG), which induces immunogenic cell death (ICD), stimulates the phagocytosis of DC cells, and promotes specific T cell anti-tumor immunity (Ma et al., 2022). The study also showed that the mannose released by DM NG interferes with glucose metabolism and thus regulates tumor metabolism, ultimately leading to apoptosis of cancer cells. It is also pointed out that this strategy can systematically modulate the tumor microenvironment (TME) and improve the immunosuppressive tumor microenvironment (ITM).