Methyltransferases, including methyltransferase-like 3 and 14 proteins (METTL3 and METTL14, respectively) and their cofactors, such as WT1-associated protein (WTAP), Vir-like m6A methyltransferase associated (VIRMA), zinc finger CCCH-type containing 13 (ZC3H13), and RNA-binding motif protein 15/15B (RBM15/15B), play a crucial role in the composition of the methyltransferase complex (MTC), thereby catalyzing the modification of adenosine on mRNA to form m6A (31, 32). METTL3, METTL14, and WTAP are the core proteins of m6A methyltransferase, and they function together to form the MTC (33). In 1997, Joseph et al. discovered METTL3 as the most important and first known component of this complex (34, 35). Interestingly, METTL16, which shares homology with METTL3, has been identified as a novel, independent RNA methyltransferase that regulates cellular S-adenosylmethionine levels and methylates U6 small nuclear RNA (36). One study found that platelet-derived growth factor signaling impedes mitophagy in glioblastoma stem cells by regulating N6-methyladenosine, thereby potentially contributing to the tumorigenic properties and survival of these cells (37).This intricate network of methyltransferases and their associated proteins highlights their essential role in mRNA modifications, which are critical for various cellular processes and could be a potential target for therapeutic interventions in tumors.

Demethylases, such as fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5), play crucial roles in demethylating bases that undergo m6A modifications (38). FTO was the first protein discovered to catalyze the demethylation of m6A, and it collaborates with ALKBH5 to regulate m6A levels in the transcriptome (5, 39, 40). The demethylation function of ALKBH5, the second demethylase identified after FTO, tends to be targeted toward tRNA, rather than mRNA or rRNA (41). ALKBH5 has been implicated in the regulation of lncRNAs, cancer stem cells, autophagy, and hypoxia (42). Lv D et al. conducted that the epidermal growth factor receptor (EGFR) promotes the nuclear retention of ALKBH5 in glioblastoma. This retention leads to a reduction in m6A levels, thereby protecting glioblastoma cells against ferroptosis, a form of regulated cell death involving iron-dependent lipid peroxidation (43). Moreover, this protein was found to modify PD-L1 via mRNA epigenetics, suggesting its potential role in immunotherapy responses, which could provide new insights into cancer immunotherapy (44). The study of demethylases and their roles in m6A modifications and transcriptome regulation provides exciting possibilities for understanding the epigenetic mechanisms involved in various cellular processes, including cancer development and immunotherapy. Further research in this area could reveal novel therapeutic targets and treatment strategies for cancer and other related diseases.

m6A-modified RNA requires specific m6A-binding proteins for recognition to perform specific biological functions. These proteins are known as m6A readers (45). Among m6A readers, the YT521-B homology (YTH) domain family includes YTHDC1, YTHDC2, YTHDF1, YTHDF2, and YTHDF3, which has a conserved m6A binding domain (46). Heterogeneous nuclear ribonucleoprotein family proteins (HNRNPs) and eukaryotic initiation factor 3 (eIF3) are the key m6A readers (47). The functions of these m6A reader proteins mainly involve specific binding to the m6A methylation region on RNA, weakening homologous binding to RNA-binding proteins, and altering the RNA secondary structure to modulate protein–RNA interactions (48). These interactions between m6A readers and modified RNA play crucial roles in various cellular processes, including the regulation of gene expression, RNA splicing, mRNA stability, and translation. Accordingly, understanding the mechanisms of m6A reader proteins is essential to elucidate the epigenetic regulatory networks governed by m6A modifications and their impact on cellular functions and disease development.

Glucose metabolism plays a crucial role in overall metabolic processes, as it pertains to one of the three major energy substrates in the body. Glycolysis is the primary pathway of glucose metabolism, and its end product, pyruvate, can be converted to lactic acid in the absence of oxygen or can enter the TCA cycle for oxidative phosphorylation. Despite producing a lower amount of ATP than aerobic oxidation, glycolysis has a much faster ATP production rate, allowing for the generation of many metabolites to provide energy for tumor initiation and development. This explains why tumors often utilize anaerobic glycolysis even in the presence of ample oxygen. Consequently, targeting glycolysis has emerged as a potential strategy for tumor therapy.

Under pathological conditions, cancer cells increase glucose uptake, making it possible to detect tumors using positron emission tomography and evaluate the tumor response (53). Key enzymes involved in glucose metabolism and their related target genes can regulate metabolic processes, thereby influencing tumor growth characteristics. For example, hexokinase II (HKII), aldehyde-3-phosphate dehydrogenase (GAPDH), the pyruvate kinase (PK)-M2 isoform, and lactate dehydrogenase (LDH) play crucial roles in regulating glucose metabolism. In addition, the cisplatin-induced p53-mediated downregulation of HKII expression affects chemotherapy sensitivity in ovarian cancer (54). Moreover, GAPDH plays a vital role in tumor cell survival, angiogenesis, and the post-transcriptional regulation of tumor cell mRNA. Additionally, LDHA phosphorylation and activation can promote cancer cell invasion and metastasis, making it a potential therapeutic target and prognostic marker for human cancers (55). The Fibrillin-1/VEGFR2/STAT2 signaling axis enhances chemoresistance in ovarian cancer by regulating glycolysis and angiogenesis within both organoids and cancer cells (56).The study by Zhen Y et al. suggests that oncogenic Fibroblast Growth Factor Receptor 2(FGFR2) signaling drives NF-κB-dependent glycolysis in intrahepatic cholangiocarcinoma and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities (57). Understanding the intricate mechanisms underlying glucose metabolism and the associated enzymes in cancer cells provides valuable insights into potential therapeutic targets for cancer treatment.

Lipid metabolism can be divided into two main processes, anabolism and catabolism. In cancer, tumor cells exhibit altered lipid metabolism to meet specific needs. For example, as tumor cells proliferate, they increase fatty acid synthesis to support cell growth and reproduction. Fatty acids play crucial roles in energy storage, cell membrane synthesis, and signaling molecule production (25).

Fatty acid β-oxidation is a significant pathway involved in fat breakdown, and tumor cells utilize the energy generated through this process to fuel their biological activities, including proliferation and invasion. The proper regulation of lipid metabolism, including fatty acid uptake, hydrolysis, and synthesis, is essential for maintaining cellular homeostasis (58). Energy stored in fat primarily exists in the form of fatty acids, which are taken up by tissues through various transporters, such as cluster of differentiation 36 (CD36), the FA transport protein (FATP) family, and plasma membrane fatty acid-binding proteins (FABPs) (59). Notably, blocking CD36 with neutralizing antibodies has been shown to inhibit oral cancer metastasis (60).

Studies have demonstrated that lipid metabolism has a significant effect on tumor progression and resistance to therapy. For example, Wang et al. found that inhibiting the JAK/STAT3 pathway could regulate breast cancer self-renewal and the expression of genes related to lipid metabolism, ultimately affecting fatty acid oxidation and chemotherapy resistance (61). Similarly, in acute myeloid leukemia (AML) and ovarian cancer, the overexpression of fatty acid-β-oxidation-related enzymes, such as CPT1A, has been associated with poor patient prognosis (62). Moreover, in various cancer types, the inhibition of CPT1 significantly inhibits cell growth and viability (63, 64).Moreover, oncogene amplification in growth factor signaling pathways drives cancer cells to depend on membrane lipid remodeling for proper function (65). This dependency suggests new targets for therapeutic intervention in cancer treatment. These findings highlight the importance of lipid metabolism in tumor biology and provide potential targets for cancer therapy. Understanding the intricate regulation of lipid metabolism in cancer cells could lead to the development of novel therapeutic approaches and strategies to combat cancer progression and enhance treatment efficacy.

Increasing studies have revealed that amino acids, such as glutamine, serine, and glycine, are not only substrates for protein synthesis but also important metabolites and metabolic regulators that support cancer cell growth. Among these amino acids, glutamine is a key metabolic regulator of cancer and is involved in various pathways, including energy metabolism, signal transduction, and the biosynthesis of cancer cells (66). Son et al. reported that in pancreatic cancer, oncogenic KRAS regulates glutamine metabolic reprogramming by transcriptionally upregulating aspartate aminotransferase (AST) expression and inhibiting glutamate dehydrogenase 1 (GLUD1) (67). Additionally, the absence of liver kinase B1 (LKB1) was found to lead to the induction of a growth-promoting metabolic program in proliferating cells. Cells lacking LKB1 exhibit the increased uptake and utilization of glucose and glutamine, which supports elevated cellular ATP levels and increased macromolecule biosynthesis (68). In the context of T cell acute lymphoblastic leukemia, the inhibition of serine hydroxymethyltransferase (SHMT), a key enzyme involved in serine metabolism, has shown a synergistic anti-tumor effect with methotrexate (69). Similarly, targeting SHMT revealed a specific metabolic vulnerability in diffuse large B cell lymphoma (70). These findings underscore the significance of amino acids, especially glutamine, serine, and glycine, as vital components of cancer cell metabolism and as potential targets for therapeutic interventions.

Nucleotide metabolism plays a critical role in various biological processes, including DNA replication, repair, and cellular signaling. Aberrant nucleotide metabolism has been implicated in the development and progression of various tumors (71). Nucleotide metabolism involves the synthesis, breakdown, and recycling of nucleotides, which are essential for the maintenance of cellular functions (72, 73). In tumor cells, changes in nucleotide metabolism can lead to genomic instability, cell proliferation and resistance to anticancer therapies. Targeting nucleotide metabolism, especially in tumor immunotherapy, is a promising new direction to enhance immune efficacy (74).

Nucleotide synthesis occurs through two main pathways: de novo synthesis and salvage pathways. Several key enzymes and pathways in nucleotide metabolism have been identified to play a crucial role in tumor development and progression.High levels of hypoxanthine-guanine phosphoribosyltransferase (HPRT), an enzyme involved in the salvage pathway, have been detected in lung cancer cells. This contributes to the increased synthesis of nucleotides, which are essential for rapid cellular proliferation. Targeting HPRT may offer a novel therapeutic approach for treating lung cancer (75).It has been highlighted that blocking equilibrative nucleoside transporter 1 with CNX-774 can overcome resistance to dihydroorotate dehydrogenase inhibition, offering a promising approach to treating pancreatic cancer that has become resistant to current therapeutic strategies (76).Nathanson DA et al. explored the strategy of simultaneously targeting multiple convergent nucleotide biosynthetic pathways, which could be a potent approach for eradicating leukemia by exploiting the vulnerabilities in cancer cells’ nucleotide synthesis, thereby enhancing the effectiveness of treatment (77). Surprisingly, Keshet R et al. reveal that the suppression of purine synthesis not only raises the pyrimidine to purine ratio but also boosts the expression of the immunoproteasome. Consequently, this leads to a notable augmentation in the responsiveness of autologous primary CD8+T cells to anti-PD-1 treatment. The findings imply that patients with high-Argininosuccinate synthase1 expressing cancers could derive advantage from purine synthesis inhibitors, potentially making them more receptive to immune checkpoint blockage therapies (78).Therefore, targeting nucleotide metabolism holds promise for enhancing cancer treatment by contributing to genomic stability, overcoming drug resistance, and improving immune therapy efficacy.

Respiratory system tumors include various malignancies, such as nasopharyngeal, lung, and laryngeal cancers. Non-small cell lung cancer (NSCLC) is associated with the highest mortality rate worldwide. Research has revealed that m6A RNA methylation plays a critical role in NSCLC progression by regulating mitochondrial RNA processing endonuclease (RMRP) stability and affecting the TGFBR1/SMAD2/SMAD3 pathway (103). Ma et al. showed that the dysregulation of METTL3, ALKBH5, and YTHDF1-mediated ENO1 translation creates a favorable metabolic environment in lung adenocarcinoma cells, promoting glycolysis and facilitating tumor occurrence and progression (85).

Further, the dysregulation of this pathway contributes to cancer progression and metastasis in NSCLC, which is associated with a high mortality rate worldwide. Li et al. observed upregulated expression of WTAP in nasopharyngeal carcinoma and found that it methylates DIAPH1-AS1 in a manner dependent on the m6A reader IGF2BP2, subsequently enhancing its stability. This, in turn, promotes the formation of the MTDH–LASP1 complex, leading to the upregulation of LASP1 expression and ultimately promoting the growth and metastasis of nasopharyngeal carcinoma (104). Regarding laryngeal carcinoma, the methyltransferase domain of YTHDF1 has been shown to interact with the 3′-UTR and 5′-UTR of TRFC mRNA, resulting in the promotion of its translation. Experimental validation further suggested that TFRC serves as a key target of YTHDF1-mediated increases in iron metabolism (105). These findings highlight the critical involvement of m6A RNA methylation in the progression and metastasis of respiratory system tumors. Understanding the molecular mechanisms underlying these processes could lead to the identification of potential therapeutic targets and strategies for treating aggressive malignancies.

In recent years, numerous studies have highlighted the significant role of m6A modifications in the occurrence and development of digestive system tumors. Guo et al. identified heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as an m6A reader that promotes the proliferation, migration, and invasion of esophageal cancer by upregulating expression of the fatty acid synthases ACLY and ACC1 (86). In esophageal squamous cell carcinoma, Wang et al. found that METTL3 enhances the m6A modification of APC and recruits YTHDF for APC mRNA degradation. In turn, decreased APC expression increases β-catenin and β-catenin-mediated cyclin D1, c-Myc, and PKM2 expression, leading to enhanced aerobic glycolysis in mice, which ultimately promotes cell proliferation and tumor formation (87).

In gastric cancer, WTAP, as an m6A methyltransferase, enhances the stability of HK2 mRNA by binding the 3′-UTR m6A site, thereby promoting the proliferation and glycolysis of gastric cancer (88). In hepatocellular carcinoma, HBXIP drives the metabolic reprogramming and malignant biological behavior of cancer cells by positively regulating the METTL3-mediated m6A modification of HIF-1α (106). Moreover, Zuo et al. reported that in this malignancy, METTL3 regulates the m6A modification of LINC00958, enhancing its stability, and that LINC00958 ultimately promotes cancer cell adipogenesis by upregulating the expression of HDGF (90).

Guo et al. found that METTL3 stimulates the m6A modification of DEGS2 and that YTHDF2 binds to the m6A site, promoting DEGS2 decay. As a result, ceramide synthesis was found to be increased due to the downregulation of DEGS2 expression (107). Additionally, Shen et al. demonstrated that METTL3 stabilizes the expression of HK2 and GLUT1 in colorectal cancer through an m6A–IGF2BP2/3-dependent mechanism, thereby regulating glucose metabolism (91). Moreover, the N6-methyladenosine reader IMP2 activates the Warburg effect by stabilizing the ZFAS1/OLA1 axis (92).

Research on m6A modifications in reproductive system tumors, including cervical, ovarian, and prostate cancers, is ongoing. Wang et al. reported that METTL3 enhances the stability of HK2 through YTHDF1-mediated m6A modifications, promoting the Warburg effect in cervical cancer (93). Additionally, the downregulation of E6/E7 and IGF2BP2 expression has been shown to decrease aerobic glycolysis capacity and the growth of cervical cancer cells. Mechanistically, the E6/E7 protein was found to regulate MYC mRNA m6A modifications through IGF2BP2, thus promoting cervical cancer cell aerobic glycolysis, proliferation, and metastasis. That study further highlighted the role of E6/E7 in promoting cervical cancer by activating IGF2BP2 and established a link with the promotion of aerobic glycolysis (95).

In ovarian cancer, HIF-1α has been found to regulate the overexpression of WTAP in an m6A-dependent manner, thereby promoting the Warburg effect in tumors. The underlying mechanism involves an interaction between WTAP and DGCR8 to regulate miR-200 expression in an m6A-dependent manner. Simultaneously, miR-200 positively regulates the key glycolytic enzyme HK2, ultimately affecting the intracellular Warburg effect (96).

Research by Liu et al. on prostate cancer revealed that METTL3 promotes the stability of lncRNA SNHG7 through an m6A modification, and this stable lncRNA accelerates glycolysis in prostate cancer through the SRSF1/c-Myc axis (97). Furthermore, ALKBH5 overexpression inhibits cervical squamous cell carcinoma growth and lipid metabolism both in vivo and in vitro. Mechanistically, ALKBH5 inhibits ACC1 deacetylation by promoting SIRT3 methylation, and the resulting downregulation of ACC1 expression ultimately inhibits tumor growth, lipid metabolism, and tumorigenesis (94).

M6A modifications also play a significant role in the regulation of metabolism within the urinary system. Zhang et al. demonstrated that the downregulation of METTL14 expression in renal cell carcinoma might be linked to tumor development and metabolic regulation. Notably, METTL14 deficiency was found to promote the metastasis of renal cell carcinoma in both in vivo and in vitro experiments. Mechanistically, METTL14-mediated m6A modifications were shown to have a negative regulatory effect on the stability of bromine PHD finger transcription factor (BPTF) mRNA, with BPTF playing a pivotal role in pulmonary metastasis. BPTF functions as a super-enhancer that activates downstream targets, including enolase 2 and SRC proto-oncogene non-receptor tyrosine kinase, thereby leading to the glycolytic reprogramming of METTL14^−/− cells (98). Yuan et al. demonstrated that the m6A-modified reader IGF2BP1 promotes glycolysis, which involves glucose uptake, lactic acid production, and extracellular acidification. Mechanistically, IGF2BP1 recognizes the m6A modification site on LDHA mRNA, leading to enhanced mRNA stability and the consequent acceleration of tumor energy metabolism. Thus, m6A modulations appear to play a significant role in mediating aerobic glycolysis in clear-cell renal cell carcinoma (99). Furthermore, MTHFD2 expression was found to be significantly elevated in renal cell carcinoma, with sequencing data indicating that MTHFD2 can promote the translation of HIF-2α, thereby further enhancing aerobic glycolysis. Consequently, MTHFD2 establishes an association between the RNA methylation status in renal cell carcinoma and the metabolic state of tumor cells (100).

Expanding on our understanding of bladder cancer, ALKBH5 expression was found to be significantly downregulated, and its low expression is associated with poor prognosis in patients. Additionally, the downregulation of ALKBH5 expression promotes bladder cancer cell proliferation, migration, and invasion, resulting in reduced sensitivity to cisplatin chemotherapy. Mechanistically, ALKBH5 further regulates the casein kinase 2 (CK2) α-mediated glycolysis pathway by mediating the stability of CK2α, ultimately inhibiting bladder cancer progression in an m6A-dependent manner and increasing cisplatin sensitivity (101). Moreover, Liu et al. identified METTL14 as a primary m6A-related enzyme in bladder cancer. Mettl14-mediated m6A modifications were found to promote the expression of lncDBET, and the upregulation of lncDBET expression activates the PPAR signaling pathway, which, through a direct interaction with FABP5, promotes lipid metabolism in cancer cells, thus driving the malignant progression of BCa both in vitro and in vivo (102).

In addition to solid tumors, for hematological tumors, a series of studies have also reported the regulation of m6A methylation modification in metabolism.For example, the m6A reader IGF2BP2 modulates glutamine metabolism in acute myeloid leukemia (AML), and targeting IGF2BP2 could serve as a novel therapeutic strategy for the disease (108).Moreover, METTL16 drives the development of leukemia and the self-renewal of leukemia stem cells by reprogramming the metabolism of branched-chain amino acids. This metabolic reprogramming identifies METTL16 as a potential therapeutic target for combating leukemogenesis (109).m6A modification of circTET2, by interacting with HNRNPC, orchestrates fatty acid oxidation to enhance the proliferation of chronic lymphocytic leukemia. This mechanism highlights circTET2 as a novel therapeutic target for managing the disease (110).Furthermore, R-2-hydroxyglutarate dampens aerobic glycolysis in leukemia through the FTO/m6A/PFKP/LDHB signaling axis, offering a potential therapeutic approach for modulating leukemia metabolism (111).

In addition to the above studies, in our nervous system tumors, In addition, ALKBH5, FTO, YTHDF2 and other key enzymes that regulate m6A methylation play an indispensable regulatory role in the occurrence and development of glioma. Therefore, it may provide more diversified options for the treatment of glioma (112–114). However, there are limited reports on the regulation of m6A methylation modification on metabolism in gliomas.Ruan C et al’s research highlights the role of METTL3 in promoting aerobic glycolysis in glioma cells through the regulation of the m6A/miR-27b-3p/PDK1 signaling pathway, which is crucial for the tumorigenic metabolism and proliferation of glioma cells (115).Interestingly, a study by Zhang J et al. found cholesterol metabolism plays a critical role in glioma malignancy, with the hnRNPA2B1 protein acting as a key regulator. It demonstrates that hnRNPA2B1-dependent regulation of the sterol regulatory element-binding protein 2 (SREBP2) and the low-density lipoprotein receptor (LDLR) contributes to the dysregulation of cholesterol metabolism, thereby promoting the malignant characteristics of glioma cells (116). Meanwhile, another recent study showing the forced expression of malate dehydrogenase 2(MDH2) raised m6A levels and suppressed ALKBH5 activity in glioblastoma stem cells, which could be restored by alpha-ketoglutarate supplementation. Conversely, targeting MDH2 decreased overall m6A levels and affected the expression of platelet-derived growth factor receptor-β. Inhibiting MDH2 in glioblastoma stem cells enhanced the effectiveness of dasatinib, a multi-kinase inhibitor, suggesting a potential therapeutic approach for targeting stem-like tumor cells by reprogramming their metabolism (117).

These studies collectively demonstrate the crucial role of m6A modifications in the metabolic reprogramming and progression of various tumors. Further investigations in these areas hold great potential for advancing our understanding of tumor biology and developing novel therapeutic strategies.

Macrophages are essential regulators of the immune system and include classically activated macrophages (M1) and alternatively activated macrophages (M2), the polarization of which influences the occurrence and development of various diseases. M1 macrophages can kill tumor cells and facilitate resistance to pathogen invasion, whereas M2 macrophages predominantly contribute to tumor growth, invasion, and metastasis (133). Tumor-associated macrophages (TAMs) comprise a prominent population of macrophages that infiltrate tumor tissues, representing the largest number of immune cells within the tumor microenvironment. TAMs secrete various cytokines and play a role in recognizing and clearing tumor cells in the early stages of tumor development. However, as tumors progress, they also play a significant role in promoting tumor growth, invasion, and metastasis, rendering TAMs a “double-edged sword” of tumor occurrence and development (134).

METTL3 depletion in macrophages reshapes the tumor microenvironment by enhancing M1- and M2-like TAM phenotypes (122). Liu et al. reported that in pancreatic ductal adenocarcinoma, lncRNA-PACERR increases the number of M2-type polarized cells and promotes cell proliferation, invasion, and migration both in vivo and in vitro. Mechanistically, IGF2BP2 enhances the cytoplasmic stability of KLF12 and c-Myc by binding to lncRNA-PACERR in an m6A-dependent manner (124). Cui et al. showed that METT13-deficient mice exhibit increases in M1/M2-like TAMs and regulatory T-cell infiltration compared to those in wild-type mice. Mechanistically, METTL3 loss affects YTHDF1-mediated SPRED2 translation, thereby enhancing NF-kB and STAT3 activation via the ERK pathway (122).

DCs are primarily responsible for antigen processing and presentation and the activation of T cell immune responses (135). These cells play different roles at various stages of maturation. For example, immature DCs induce immune tolerance, mature DCs activate and stimulate immune responses, and regulatory DCs suppress immune responses by inhibiting T-cell responses (136).

m6A modifications play a crucial role in tumor immunomodulation, particularly in immune regulation involving DCs. For example, the methyltransferase METTL3 promotes DC activation and function. Mechanistically, the METTL3-mediated m6A modification of the CD40, CD80, and TLR4 signaling adaptor Tirap transcripts enhances their translation in DCs, thereby stimulating T-cell activation and enhancing TLR4/NF-κB signaling-induced cytokine production (137). The knockout of YTHDF1 in DCs enhances the cross-presentation of tumor antigens in vivo and the cross-activation of CD8⁺ T cells (138). In YTHDF1-deficient melanoma or colon cancer, antigen cross-presentation by tumor-infiltrating DCs induces a stronger anti-cancer immune response and mature YTHDF1-deficient DCs can activate T cells more effectively than wild-type cells, leading to stronger anti-tumor immunity (125). A separate study also demonstrated that mice lacking YTHDF1 exhibit an elevated and more effective CD8⁺ T-cell response against tumor-specific antigens. This phenomenon was attributed to a specific mechanism involving RNA methylation (m6A modification), in which transcripts encoding lysosomal proteases are marked. YTHDF1 was further found to bind to these modified transcripts, subsequently leading to the increased translation of lysosomal pepsin within DCs. Interestingly, the inhibition of cathepsin, a protein involved in cellular processes, notably heightens the cross-presentation ability of normal DCs. Furthermore, the positive effect of blocking the PD-L1 checkpoint pathway was found to be notably enhanced in mice lacking the YTHDF1 gene (YTHDF1^−/− mice). This observation suggests that YTHDF1 might serve as a promising target for enhancing the effectiveness of anti-cancer immunotherapies (126).

DC-specific lnc-Dpf3 facilitates chemokine receptor 7 (CCR7)-mediated DC migration, leading to an excessive adaptive immune response and inflammatory damage. Mechanistically, YTHDF2 reduces the expression level of lnc-Dpf3 in resting mature DCs. However, CCR7 can upregulate the expression of lnc-Dpf3 by removing m6A modifications, thus stimulating the rapid but transient migration of DCs to the draining lymph nodes (139). Therefore, further exploration of the crucial regulatory role of m6A in dendritic cells could lead to innovative anti-tumor approaches.

NK cells are the cornerstone of natural immunity and constitute approximately 5–15% of the lymphocyte population. They possess the unique ability to promptly and directly eliminate foreign entities, such as virus-infected cells, cancer cells, and senescent cells, without the need for antigen presentation (140). Ma et al. revealed the importance of YTHDF2 in NK cells, showing that its deficiency can compromise their in vivo anti-tumor and antiviral activities. The underlying mechanism was determined to involve YTHDF2 promoting NK cell functions through the formation of a STAT15–YTHDF5 positive feedback loop, which is crucial for IL-2-mediated NK cell survival and proliferation (127). Moreover, m6A methylation plays a protective role in NK cell homeostasis and tumor immune surveillance. METTL3 in NK cells is essential for maintaining homeostasis, as it promotes the infiltration and functionality of NK cells in the TME, thereby enhancing anti-tumor immunity and increasing overall survival in mice (129). In addition, FTO serves as a significant regulator of NK cell immunity. In vivo studies have shown that FTO knockout in mouse NK cells prevents melanoma metastasis, whereas in vitro experiments have indicated that FTO-deficient human NK cells exhibit an enhanced anti-tumor response to leukemia, thereby providing a promising strategy for allogeneic NK cell therapy (128). In ovarian carcinoma, the depletion of METTL3 in NK cells inhibits cell infiltration ability and functions, leading to accelerated tumor development through a reduction in SHP-2 expression and AKT and MAPK signaling pathway activation (129). Therefore, the modulation of NK cells by modifying m6A methylation could be a promising anti-cancer therapeutic strategy.

MDSCs are a heterogeneous group of myeloid cells with immunosuppressive activity that have been identified as potential precursors of DCs, macrophages, and granulocytes (141). Within the TME, MDSCs play a critical role in suppressing immune cells and protecting tumors, leading to immunotherapy resistance and tumor progression, ultimately contributing to patient mortality (141). As such, targeting and eliminating MDSCs have emerged as promising strategies to improve response rates to cancer treatments and enhance patient survival (142).

Chen et al. showed that METTL3 enhances the expression of BHLHE41 by facilitating m6A modifications, subsequently leading to the increased transcription of CXCL1 and CXCR2. This enhances the migration and accumulation of MDSCs in the tumor microenvironment, ultimately suppressing the activation and proliferation of CD8+ T cells and other immune cells. The suppression of anti-tumor immunity by METTL3 through the m6A–BHLHE41–CXCL1/CXCR2 axis contributes to tumor immune evasion and progression (130). Targeting YTHDF1 enhances the anti-tumor immune response and increases the effectiveness of anti-PD-1 therapy, providing a potential novel strategy for the treatment of colorectal cancer (143). The inhibition of Alkbh5 was found to enhance the efficacy of cancer immunotherapy. Alkbh5 was also shown to regulate the expression of target genes in the TME and the composition of MDSCs, which can influence the response to immunotherapy (144). Furthermore, the knockout of METTL3 in CD33⁺ cells attenuates MDSC differentiation and the generation of tumor-associated MDSCs in vitro (145). Overall, targeting MDSCs through m6A methylation modification appears to have significant potential for improving the efficacy of anti-tumor therapy. These studies provide an understanding of the intricate regulatory role of m6A RNA methylation in the modulation of MDSCs and its effect on tumor immunity.

B cells play a central role in humoral immunity, primarily by secreting antibodies, presenting soluble antigens, and regulating immune responses. This section provides a comprehensive review of the involvement of the three major m6A RNA modifiers in B-cell development and B cell-related diseases. The germinal center (GC) is responsible for generating protective antibodies with long-lasting immune effects. Grenov et al. demonstrated that YTHDF2-mediated m6A modifications are crucial for GC maintenance. In the absence of YTHDF2, the expression of genes related to cell proliferation and oxidative phosphorylation in GC B cells is reduced, resulting in slowed cell cycle progression (146). Interleukin-7 (IL-7) induces B cell transformation, and Mettl14 is essential for this process. Accordingly, its deficiency affects B-cell development and leads to abnormalities in critical gene expression programs during B-cell maturation (147). Additionally, Yin et al. showed that the downregulation of hnRNPA2/B1 expression can lead to the inactivation of the AKT and STAT3 signaling pathways, which subsequently reduces the expression of B cell lymph-2 (Bcl-2), ultimately inhibiting the growth of glioma. These findings highlight the potential of hnRNPA2/B1 as a therapeutic target for glioma treatment (131).

Overall, this research emphasizes the importance of m6A RNA modifications in B-cell biology. It further highlights the potential of targeting B cells for immune regulation as a promising direction for anti-tumor therapy. Understanding the molecular mechanisms involved in m6A RNA modifications with respect to B-cell development and functions might thus provide valuable insights for the development of novel immunotherapeutic strategies against B cell-related diseases and cancer.

T cells, also known as T lymphocytes, are derived from lymphocyte stem cells in the bone marrow and undergo differentiation and maturation in the thymus. They are distributed to various immune organs and tissues throughout the body via the lymph and blood circulation systems, where they perform critical immune functions (148). In both in vitro and in vivo studies, the inhibition of METTL3 or IGF2BP3 was shown to enhance anti-tumor immunity through the PD-L1-mediated activation, depletion, and infiltration of T cells (149). In NSCLC, m6A-modified circIGF2BP3 promotes the deubiquitination of PD-L1, leading to immune evasion and resistance to treatment utilizing CD8⁺ T cells (132). The loss of METTL3 also disrupts T-cell homeostasis and differentiation, as observed by Li et al. (150). Furthermore, regulation of the m6A methyltransferase Mettl14 in TAMs can promote CD8⁺ T cell dysfunction and tumor progression (151). Methionine metabolism-derived S-adenosylmethionine promotes m6A methylation and the translation of immune checkpoints, including PD-L1 and the V-domain Ig suppressor of T cell activation (VISTA), in tumor cells. For example, the depletion of MRD or the m6A-specific binding protein YTHDF1 inhibits tumor growth by restoring CD8⁺ T-cell infiltration and, when combined with PD-1 blockade, this results in improved tumor control (152).

Overall, these findings emphasize the crucial role of m6A RNA modifications in regulating T-cell functions and immune responses in various cancers. Understanding the complex interactions between m6A modifiers and immune checkpoints will provide valuable insights into the development of new immunotherapeutic strategies for cancer treatment. However, further research is required to fully explore the potential of m6A RNA modifications as targets for cancer immunotherapy.