The crosstalk between the tumour immune microenvironment (TIME) and tumour cells promote immune evasion and resistance to immunotherapy in gastrointestinal (GI) tumours. Post-transcriptional regulation of genes is pivotal to GI tumours progression, and RNA-binding proteins (RBPs) serve as key regulators via their RNA-binding domains. RBPs may exhibit either anti-tumour or pro-tumour functions by influencing the TIME through the modulation of mRNAs and non-coding RNAs expression, as well as post-transcriptional modifications, primarily N6-methyladenosine (m6A). Aberrant regulation of RBPs, such as HuR and YBX1, typically enhances tumour immune escape and impacts prognosis of GI tumour patients. Further, while targeting RBPs offers a promising strategy for improving immunotherapy in GI cancers, the mechanisms by which RBPs regulate the TIME in these tumours remain poorly understood, and the therapeutic application is still in its early stages. This review summarizes current advances in exploring the roles of RBPs in regulating genes expression and their effect on the TIME of GI tumours, then providing theoretical insights for RBP-targeted cancer therapies.

The gut microbiota undergoes continuous variations among individuals and across their lifespan, shaped by diverse factors encompassing diet, age, lifestyle choices, medication intake, and disease states. These microbial inhabitants play a pivotal role in orchestrating physiological metabolic pathways through the production of metabolites like bile acids, choline, short-chain fatty acids, and neurotransmitters, thereby establishing a dynamic "gut-organ axis" with the host. The intricate interplay between the gut microbiota and the host is indispensable for gut health, and RNA N6-methyladenosine modification, a pivotal epigenetic mark on RNA, emerges as a key player in this process. M6A modification, the most prevalent internal modification of eukaryotic RNA, has garnered significant attention in the realm of RNA epigenetics. Recent findings underscore its potential to influence gut microbiota diversity and intestinal barrier function by modulating host gene expression patterns. Conversely, the gut microbiota, through its impact on the epigenetic landscape of host cells, may indirectly regulate the recruitment and activity of RNA m6A-modifying enzymes. This review endeavors to delve into the biological functions of m6A modification and its consequences on intestinal injury and disease pathogenesis, elucidating the partial possible mechanisms by which the gut microbiota and its metabolites maintain host intestinal health and homeostasis. Furthermore, it also explores the intricate crosstalk between them in intestinal injury, offering a novel perspective that deepens our understanding of the mechanisms underlying intestinal diseases.

Ferroptosis is an apoptosis-independent cell death pathway characterized by heightened lipid peroxidation, which shows promise for tumor suppression. Despite extensive research on long non-coding RNAs (LncRNAs) in ferroptosis, their role in colorectal cancer (CRC) remains underexplored. We investigated the upregulation of AC145207.5 and HNRNPC expression in CRC tissues through public dataset analysis and in-house validation, identifying them as having significant diagnostic potential. In vitro experiments including MTS assay, transwell, and colony formation, alongside in vivo studies using xenograft models, elucidated the synergistic carcinogenic role of the HNRNPC/AC145207.5 axis in promoting the malignant characteristics of CRC. Mechanistically, the m6A reader HNRNPC stabilized m6A-modified AC145207.5, contributing to its stabilization and upregulation. Consequently, AC145207.5 activated the Nrf2/GPX4 axis, resulting in increased GPX4 expression, inhibition of GPX4-mediated ferroptosis, and facilitation of CRC progression. Our findings underscore the clinical relevance of the HNRNPC/AC145207.5 axis in CRC and illuminate its regulatory role in ferroptosis, suggesting implications for targeted precision medicine in CRC.

An impressive clinical success has been achieved in the treatment of various cancers employing immunotherapy and checkpoint blockade antibodies. However, limited therapeutic response has been observed in most of the patients receiving anti-PD1 antibodies remains a critical challenge, underscoring the need for innovative strategies to enhance immunotherapeutic efficacy to overcome these barriers. Several epigenetic drugs targeting DNA and histone proteins have received FDA approval are in the market. However epigenetic drugs targeting mRNA-modification machineries are still in infancy. The discovery of RNA modification enzymes (writers, erasers, and readers) has refuelled the scientific horizons in overcoming the challenges mainly associated with other pharmaceutical drugs. RNA modification especially 'm6A' is one of the well-studied epitranscriptomic mechanisms involved in regulating diverse biological processes via mRNA metabolism. To date more than 170 different types of RNA-modifications have been identified covering the different aspects of cellular, immunological, and biological functions. In this review we aim to summarize the potential of utilizing m6A-modifiers in discovering novel therapeutic procedure targeting immune cell subsets. Moreover, we have highlighted the possibilities of improving personalized therapy co-targeting m6A-modifiers engineered with other intracellular checkpoint genes like CISH. Furthermore, we have proposed dual therapeutic approach combining m6A-modifiers with anti-PD1 antibodies to enhance the efficacy of targeted medicines. Additionally, we have mentioned few biopharmaceutical companies and cell therapy clinics developing m6A-based RNA-modifying drugs (RMDs) and associated clinical trials. Our study will advance foundational knowledge in nurturing the potential of 'RNA epigenetic modifiers' in discovering novel therapeutic drug candidates, enhancing personalized therapy through immune cell engineering.

Uveal melanoma (UM) is a primary intraocular malignancy with a high-risk of metastasis. Currently, there are no studies that construct prognostic models based on immune-related molecular subtypes. We performed unsupervised clustering of immune cell infiltration matrices based on the the cancer genome atlas-uveal melanoma (TCGA-UVM) dataset, identifying 2 clusters with distinct expression patterns of immune checkpoint and immune activation related genes. gene ontology/Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that genes in the immune-related gene modules identified by WGCNA were associated with immune activity and cell proliferation. Using Cox and LASSO regression analysis based on the immune-related gene modules to construct a prognostic model. The prognostic model was validated in external datasets of Gene Expression Omnibus (GEO) database. We constructed a prognostic model comprising genes S100A4, KCNIP3, PARP8, ORAI2, MMP12, ISG20, MMP9, and CEBPB. The model stratified patients into high and low-risk groups, with the high-risk group showing poorer prognosis. The model's predictive accuracy was validated with the AUC values exceeding 0.8 for 1-year, 3-year, and 5-year survival rates and confirmed in external datasets GSE22138 and GSE84976. Differential gene analysis between risk groups highlighted the association with immune response and cell proliferation functions. The CEBPB gene in the model played crucial roles in tumor progression. In vivo and in vitro experiments validated the impact of CEBPB on the biological functions of UM. Experiments in UM cells revealed that CEBPB promoted cell proliferation, migration and invasion, as well as suppressing apoptosis, indicating its potential as a therapeutic target. The prognostic model based on 8 immune-related genes effectively predicted the survival outcomes of UM. Knockdown of CEBPB significantly reduced the progression of UM, suggesting that it could be a potential therapeutic target for UM.

Tumor-infiltrating B cells (TIBs) are the most important cell type involved in the immune response. TIBs display considerable intratumor heterogeneity due to genetic variation, epigenetic differences and transcriptional plasticity in the tumor microenvironment (TME). Owing to the unique anatomical location of CRC, the B cell subpopulation exhibits more extensive heterogeneity. Many studies have shown that TIBs have gradually become a key predictor of immunotherapy for malignant cancers, including CRC. TIBs have essential functions, including antigen presentation and antibody secretion, and they promote T-cell activation and myeloid chemotaxis. However, owing to the complex TME, TIBs not only promote the antitumor immune response but also inhibit the immune response. With the in-depth study of tumor-infiltrating T cells, tumor-associated myeloid cells and the interactions among these cells in the TME, the special role of immune cells in the TME has gradually become clear. However, the influence of TIBs in the TME and their interactions with nonimmune cells in the TME remain unclear. Here, we summarize the current progress in TIBs based on single-cell RNA sequencing in CRC in recent years, focusing on specific effector or regulatory characteristics of different B cell subclusters in the CRC TME.

RNA modifications are crucial for post-transcriptional gene regulation. Research on RNA modifications has become a novel frontier of epitranscriptomics. Up to now, over 170 kinds of modifications have been identified on mRNA and diverse non-coding RNA. Three classes of proteins (writers, erasers, and readers) regulate the addition, removal, and identification of epigenetic marks, thus affecting RNA biological functions. Increasing evidence identifies the dysregulation of RNA modifications in different cancer types and the therapeutic potential of targeting RNA-modifying enzymes. The ability of RNA modifications to improve mRNA stability and translation efficacy and decrease immunogenicity has been exploited for the clinical use of mRNA cancer vaccines. This review aims to shed light on several vital cap, tail, and internal modifications of RNA with a focus on the connection between RNA epigenetic pathways and cancer pathogenesis. We further explore the clinical potential of RNA modifications as dynamic biomarkers for cancer diagnosis, prognosis, and therapeutic response prediction, addressing both technological challenges and translational opportunities. Finally, we analyze the limitations of current studies and discuss the research focus in the future.

Malignant rhabdoid tumor of the kidney (MRTK) is a rare renal tumor with poor prognosis. While germline mutations of SMARCB1 are considered to be the primary cause of MRTK, emerging evidence suggests that somatic epigenetic changes also play a vital role in the development and progression of MRTK. YTHDF1, an m6A reader protein, has been implicated in regulation of tumorigenesis by influencing RNA translation and stability in several adult cancers. However, the exploration of the role of YTHDF1 in pediatric cancer, especially MRTK, remains limited.

In this study, CRISPR/Cas9 was employed to knockout (KO) YTHDF1 in G401 cells. The impact of YTHDF1 on the cell growth and chemoresistance were assessed using CCK-8 assays. Western blot and qRT-PCR were used to determine the changes in ferroptosis marker gene expression. Additionally, 4D-label free quantitative proteomics was conducted to uncover alterations by YTHDF1 deletion.

We observed that the deletion of YTHDF1 in the MRTK cell line led to a significant reduction in malignancy-associated characteristics, including decreased cell motility, invasive growth, and chemoresistance. Quantitative proteomic analysis revealed that the glutathione-related signaling pathway was notably affected by YTHDF1 KO. Specifically, YTHDF1 KO resulted in a reduction of both mRNA and protein levels of Glutathione S-Transferase Mu 2 (GSTM2), a phase II metabolizing enzyme responsible for conjugating glutathione to electrophilic compounds. The decrease in GSTM2 levels following YTHDF1 KO increased the susceptibility of MRTK cells to ferroptosis. Notably, overexpression of GSTM2 in YTHDF1 KO cells partially restored the oncogenic phenotype of MRTK cells, underscoring its role in MRTK progression.

In summary, our findings provide new insights into the molecular mechanisms driving MRTK progression, highlighting YTHDF1 and GSTM2 as potential therapeutic targets for this aggressive pediatric renal tumor.

Drug resistance in colorectal cancer (CRC) poses a major challenge for cancer therapy and stands as the primary cause of cancer-related mortality. The N6-methyladenosine (m6A) modification has emerged as a pivotal regulator in cancer biology, yet the precise m6A regulators that propel CRC progression and chemoresistance remain elusive. Our study established a significant correlation between m6A regulatory gene expression profiles and CRC severity. Notably, based on the knockout cellular and mouse model created by CRISPR/Cas9-mediated genome engineering, we identified m6A demethylase FTO emerged as a pivotal orchestrator of CRC chemoresistance through the regulation of NUPR1, a critical transcription factor involved in iron homeostasis via LCN2 and FTH1. Mechanistic study revealed that FTO stabilized NUPR1 mRNA by specifically targeting the +451 m6A site, thereby preventing YTHDF2-mediated degradation of NUPR1 mRNA. Moreover, the simultaneous targeting of FTO and NUPR1 dramatically enhanced the efficacy of chemotherapy in CRC cells. Our findings underscore the potential of modulating the m6A methylome to overcome chemoresistance and highlight the FTO-NUPR1 axis as a critical determinant in CRC pathobiology.

Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) treatment. Recent studies have implicated CPSF6 in cancer progression and drug resistance, although its role in chemotherapy resistance and regulatory mechanisms is unclear. This study investigates CPSF6's involvement in oxaliplatin resistance in CRC and its regulation via m6A methylation by METTL3. We assessed CPSF6 expression in oxaliplatin-resistant (OxR) CRC cell lines (HT29-OxR and HCT116-OxR) compared to sensitive counterparts using qRT-PCR and Western blotting. CPSF6 was significantly upregulated in OxR cells, and its knockdown reduced cell viability, colony formation, and glycolytic activity while increasing apoptosis. m6A modification of CPSF6 mRNA was elevated in OxR cells, correlating with increased METTL3 expression. METTL3 knockdown decreased CPSF6 levels and m6A enrichment, enhancing mRNA degradation, while its overexpression stabilized CPSF6 mRNA, promoting resistance. Xenograft experiments showed that CPSF6 knockdown suppressed tumor growth and glycolysis. Thus, CPSF6 is identified as a mediator of oxaliplatin resistance in CRC, regulated by the METTL3/m6A axis, suggesting potential therapeutic targets to overcome resistance.

Colorectal cancer is the third most common malignant tumor worldwide and ranks second in terms of mortality. N6-methyladenosine (m6A) modification is the most prevalent internal covalent modification in eukaryotic mRNA and is involved in various stages of RNA processing, including splicing, degradation, and export, playing a crucial role in the onset and progression of many diseases. The m6A modification is co-regulated by methyltransferases, demethylases, and methyl-binding proteins, and it has become a hot topic in cancer research. Based on a systematic review of existing studies on the role of m6A modification in colorectal cancer, this article further expands the research horizon in this field and effectively overcomes the limitations of existing reviews that only focus on discussing a single or a class of methylation regulators.

Resistance to anti-PD-1 therapy remains a significant challenge in gastric cancer (GC) treatment. Here, we revealed that the USP14-IMP2-CXCL2 axis in tumor-associated macrophages (TAMs) drove resistance by recruiting myeloid-derived suppressor cells (MDSCs). Endoscopic biopsy samples were obtained from patients with inoperable GC who were candidates for anti-PD-1 therapy. Single-cell RNA sequencing (scRNA-seq) analysis showed a higher prevalence of USP14+ TAMs in therapy-resistant cases, where USP14 was linked to the immunosuppressive phenotype of TAMs. Clinically, GC samples with elevated USP14+ TAM infiltration exhibited decreased CD8+ T cell presence and increased MDSC infiltration. In vivo experiments further confirmed that USP14+ TAMs facilitated resistance to anti-PD-1 therapy in GC, reduced the infiltration of CD8+ T cells, and significantly increased the infiltration of MDSCs. In particular, USP14+ TAMs markedly enhanced the recruitment of MDSCs into the GC microenvironment through the secretion of CXCL2. Mechanistically, USP14 stabilized the m6A reader IMP2 through deubiquitination, thus enhancing CXCL2 expression and secretion. Conversely, the E3 ligase RNF40 facilitated IMP2 degradation via increasing its ubiquitination, with USP14 and RNF40 dynamically balancing IMP2's protein abundance. Furthermore, animal experiments demonstrated that targeted intervention of USP14 markedly enhanced the sensitivity of GC to anti-PD-1 therapy. This study provided a comprehensive exploration of USP14's oncogenic roles in TAMs, suggesting a novel strategy to enhance the efficacy of anti-PD-1 therapy by inhibiting the USP14/IMP2/CXCL2 signaling axis in GC.

The treatment of non-small cell lung cancer (NSCLC) remains a critical challenge in oncology, primarily due to the dysfunction and exhaustion of T cells within the tumor microenvironment, which greatly limits the effectiveness of immunotherapy. This study investigates the regulatory role of the T cell immunoglobulin and ITIM domain (TIGIT)-CD226-PVR signaling axis in the exhaustion and apoptosis of cluster of differentiation (CD)27+/CD127+T cells in NSCLC. Utilizing single-cell sequencing technology, we conducted a comprehensive gene expression analysis of T cells in a mouse model of NSCLC. Bioinformatics analysis revealed that the TIGIT-CD226-PVR signaling axis is highly active in the CD27+/CD127+T cell subset and is closely associated with their functional decline and exhaustion. In vitro experiments further demonstrated that inhibiting the TIGIT-PVR pathway while activating the CD226-PVR pathway significantly restored T cell proliferation and effector function. Importantly, in vivo studies showed that targeting this axis can significantly alleviate T cell exhaustion, enhance their cytotoxicity against NSCLC cells, and promote apoptosis, thereby improving the efficacy of immunotherapy.

The m6A modification is an RNA modification that impacts various processes of RNA molecules, including transcription, splicing, stability, and translation. Recently, researchers have discovered that the presence of m6A modification can influence the interaction between tumor cells and immune cells and also play a role in regulating the expression of immune response-related genes. Additionally, m6A modification is intricately involved in the regulation of tumor immune evasion and drug resistance. Specifically, certain tumor cells can manipulate the gene expression through m6A modification to evade immune system attacks. Therefore, it might be possible to enhance tumor immune surveillance and improve the effectiveness of immune-based therapies by manipulating m6A modification. This review systematically discusses the role of m6A modification in tumor immunity, specifically highlighting its regulation of immune cells and immune-related genes in tumor cells. Furthermore, we explore the potential of m6A modification inhibitors as anti-cancer therapies and the significance of m6A regulatory factors in predicting the efficacy of tumor immune therapy.

Oesophageal squamous cell carcinoma (OSCC) represents a highly aggressive malignancy with limited therapeutic options and poor prognosis. This study uncovers PCIF1 as a critical driver of OSCC progression via m6Am RNA modification, leading to translational repression of the tumour suppressor MTF2. Our results demonstrate that PCIF1 selectively suppresses MTF2 translation, activating oncogenic pathways that promote OSCC growth. In vitro and in vivo models confirm that PCIF1 knockdown reduces OSCC progression, whereas MTF2 knockdown counteracts this effect, highlighting the importance of the PCIF1-MTF2 axis. Clinical analyses further reveal that high PCIF1 expression and low MTF2 expression correlate with advanced tumour stage, poor treatment response and decreased overall survival. Furthermore, in a preclinical mouse model, PCIF1 knockout enhanced the efficacy of anti-PD1 immunotherapy, reducing tumour burden and improving histological outcomes. Notably, flow cytometry analysis indicated that PCIF1 primarily exerts its effects through tumour-intrinsic mechanisms rather than direct modulation of the immune microenvironment, distinguishing its mode of action from PD1 blockade. These findings establish PCIF1 and MTF2 as promising prognostic markers and therapeutic targets for OSCC, offering new avenues for treatment strategies and patient stratification. KEY POINTS: PCIF1 promotes OSCC progression via m6Am methylation at the MTF2 mRNA 5' cap. m6Am methylation suppresses MTF2 translation, enhancing tumour cell proliferation and invasion. Targeting PCIF1 holds therapeutic potential for OSCC treatment.

Immunotherapy has shown promising results in cancer treatment; however, it remains largely ineffective for pancreatic ductal adenocarcinoma (PDAC). N6-methyladenosine (m6A), known for its crucial role in cancer biology, is not yet fully understood regarding immune evasion. This study aims to elucidate the associations and mechanisms linking m6A modification with immune evasion in PDAC and propose strategies for clinical intervention.

A multimodal PDAC cohort of 122 patients was developed, integrating transcriptomic profiling, imaging mass cytometry, and m6A quantification to identify m6A regulators associated with immunosuppressive tumor microenvironment (TME) and clinical outcomes. Findings were validated across 6 independent PDAC cohorts. Assays including MeRIP, RIP, and RNA pull-down confirmed that IGF2BP2 binds to targets, whereas scRNA-seq, flow cytometry, and mIHC profiled the TME. Preclinical interventions were tested in PDAC organoids, patient-derived tissue fragments, and humanized mouse models.

Our comprehensive analysis identified the m6A reader protein IGF2BP2 as a critical factor associated with poor prognosis in PDAC, linked to reduced effector cell infiltration and a fibrotic TME. High matrix stiffness in PDAC stabilized IGF2BP2, which subsequently promoted sphingomyelin synthesis via SGMS2 up-regulation. This pathway facilitates PD-L1 localization on membrane lipid rafts, enhancing immune evasion. The elastographic properties of PDAC enabled noninvasive screening of patients with overexpressed IGF2BP2/SGMS2. Disrupting sphingomyelin synthesis improved antitumor immunity and suppressed PDAC growth in humanized mice, highlighting immunotherapeutic opportunities for PDAC.

These findings emphasize the critical interplay between extrinsic matrix stiffness and intrinsic IGF2BP2-regulated sphingomyelin synthesis, identifying a promising target for immunotherapeutic strategies in PDAC.

Lung cancer, a significant global health challenge, is primarily classified into non-small cell lung cancer (NSCLC) and small cell lung cancer. Despite advancements in targeted therapies and immunotherapies, NSCLC outcomes remain poor, with low five-year survival rates. Given the lung's constant exposure to the environment and the presence of mucosal-associated lymphoid tissues, immunity plays a crucial role in NSCLC development. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have shown promise. However, adverse immune events limit their efficacy. This review highlights the contrasting roles of IL-37 and IL-38 in NSCLC pathogenesis. IL-37, an anti-inflammatory cytokine, suppresses tumour growth. It achieves this by modulating macrophage polarization and dendritic cell maturation. Correlations between intra-tumoral IL-37 expression and improved survival suggest a protective role in NSCLC. This may be mediated through VEGF inhibition and immune regulation. Conversely, IL-38, while anti-inflammatory in certain contexts, exhibits a pro-tumorigenic role in NSCLC. IL-38 enhances tumour progression by increasing pro-inflammatory cytokine secretion and facilitating immune evasion, potentially through NF-κB signalling. Notably, IL-38 negatively regulates IL-37, further promoting tumorigenesis. Emerging data suggest that IL-37 has therapeutic potential in inhibiting NSCLC metastasis and supporting immune modulation. In contrast, IL-38 presents a potential target for mitigating pro-inflammatory microenvironment effects. The distinct roles of these cytokines emphasize the complex immune dynamics in NSCLC. Further exploration of their molecular mechanisms and therapeutic implications is warranted. Targeting IL-37 and IL-38 may offer novel strategies for enhancing NSCLC treatment outcomes.

T cell exhaustion (TEX) is a major barrier to effective immunotherapy. The role of N6-methyladenosine (m6A) modification in regulating immune cell function has been recognized, but its impact on TEX dynamics across cancer types and clinical outcomes remains unclear. Here, we conducted a pan-cancer analysis integrating multi-omics data from cell lines, single-cell RNA sequencing, and pan-cancer and immunotherapy datasets to explore the dynamic interplay between m6A modification and TEX. We found that m6A modification influences key TEX-associated genes at both the cellular and single-cell levels, with distinct expression patterns across the exhaustion spectrum. Based on m6A-TEX interactions, three pan-cancer subtypes were identified, each with unique molecular profiles, immune phenotypes, and survival outcomes. The TexLm6AL subtype, characterized by low m6A activity and low TEX, correlated with high immune infiltration, increased cytolytic activity, and favorable survival, whereas the TexLm6AH and TexHm6AH subtypes with higher m6A activity were associated with poorer survival. Multivariate analysis confirmed the prognostic value of this classification independent of traditional clinical factors. Moreover, m6A-TEX crosstalk influenced responses to immune checkpoint blockade therapies. Our findings provide novel insights into the role of m6A in TEX regulation and underscore the potential of m6A regulators as biomarkers and therapeutic targets for advancing cancer immunotherapy.

M6A modification is one of the most common regulatory mechanisms of gene expression in eukaryotic cells, influencing processes such as RNA splicing, degradation, stability, and protein translation. Studies have shown that m6A methylation is closely associated with tumorigenesis and progression, and it plays a key regulatory role in tumor immune responses. m6A modification participates in regulating the differentiation and maturation of immune cells, as well as related anti-tumor immune responses. In the tumor microenvironment, m6A modification can also affect immune cell recruitment, activation, and polarization, thereby promoting or inhibiting tumor cell proliferation and metastasis, and reshaping the tumor immune microenvironment. In recent years, immunotherapies for tumors, such as immune checkpoint inhibitors and adoptive cell immunotherapy, have been increasingly applied in clinical settings, achieving favorable outcomes. Targeting m6A modifications to modulate the immune system, such as using small-molecule inhibitors to target dysregulated m6A regulatory factors or inducing immune cell reprogramming, can enhance anti-tumor immune responses and strengthen immune cell recognition and cytotoxicity against tumor cells. m6A modification represents a new direction in tumor immunotherapy with promising clinical potential. This review discusses the regulatory role of m6A methylation on immune cells and tumor immune responses and explores new strategies for immunotherapy.

N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, plays a critical role in the development and progression of various diseases, including cancer, through its regulation of RNA degradation, stabilization, splicing, and cap-independent translation. Emerging evidence underscores the significant role of m6A modifications in both pro-tumorigenic and anti-tumorigenic immune responses. In this review, we provide a comprehensive overview of m6A modifications and examine the relationship between m6A regulators and cancer immune responses. Additionally, we summarize recent advances in understanding how m6A modifications influence tumor immune responses by directly modulating immune cells (e.g., dendritic cells, tumor-associated macrophages, and T cells) and indirectly affecting cancer cells via mechanisms such as cytokine and chemokine regulation, modulation of cell surface molecules, and metabolic reprogramming. Furthermore, we explore the potential synergistic effects of targeting m6A regulators in combination with immune checkpoint inhibitor (ICI) therapies. Together, this review consolidates current knowledge on the role of m6A-mediated regulation in tumor immunity, offering insights into how a deeper understanding of these modifications may identify patients who are most likely to benefit from immunotherapies.

Colorectal cancer (CRC) is a common malignant tumor. N6-Methyladenosine (m6A) modification plays an important role in the regulation of glycolysis in tumor cells and may be a potential target for tumor therapy.

The role of METTL14, an m6A writer, in CRC was investigated through functional assays including cell viability, colony formation, and glycolysis-related measurements (glucose uptake, lactate production, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR)). The target gene regulated by METTL14 in an m6A-dependent manner was identified using molecular biology techniques. In addition, CRC cells overexpressing METTL14 were subcutaneously injected into mice to verify the regulatory effect of METTL14 on tumor growth in vivo.

Our data suggested that METTL14 was up-regulated in CRC cell lines, and over-expression of METTL14 suppressed cell proliferation and glycolysis. Meanwhile, ATF2 m6A level was significantly up-regulated by over-expression of METTL14, and the binding relationship between ATF2 and METTL14 was further verified. METTL14-m6A regulated ATF2 in CRC cells participates in the regulation of glycolysis. METTL14 also suppressed tumorigenesis of nude mice.

Intervention with METTL14 mediated m6A modifications or its associated protein ATF2 may provide new strategies for CRC therapy.

Radiotherapy is one of the most effective treatments for malignant tumors. Radioresistance is a major factor that contributes to radiotherapy failure and poor prognosis. Recent studies have elucidated the pivotal role of aberrant N6-methyladenosine (m6A) modification, the predominant internal mRNA modification in eukaryotic cells, influences cancer progression by disrupting gene expression and other critical cellular processes. Furthermore, aberrant m6A methylation provides a substrate for tumor therapy; however, whether it regulates tumor radioresistance remains unclear. Methylated transferase (writer), demethylated transferase (eraser), and methylated recognition protein (reader) are the three essential proteins that regulate m6A modification via different mechanisms in different tumors. This review summarizes the latest research advances in m6A methylation and aims to provide novel perspectives on the advancement of regimens to overcome radioresistance and tumor invasion.

Colorectal cancer (CRC), characterized by its complex genetic heterogeneity and varied responses to treatment, is a leading cause of cancer-related mortality worldwide. The role of N1-methyladenosine (m1A)-related genes in tumor biology remains underexplored. This study aimed to investigate the prognostic value of m1A-related genes in CRC, characterize their role in tumor molecular subtyping, and explore their influence on the tumor microenvironment (TME) and immune infiltration.

To identify prognostic markers, univariate Cox analysis was performed using multiple datasets, including TCGA and GEO, identifying 43 m1A-related genes. Four distinct molecular subtypes of CRC were defined based on the expression of these genes using non-negative matrix factorization (NMF). Immune infiltration analysis was conducted, and the TIDE algorithm was used to predict response to immune checkpoint inhibitors (ICIs). Furthermore, a prognostic model based on m1A-related genes was constructed and validated across multiple datasets.

The results demonstrated that the four CRC molecular subtypes exhibited significant differences in survival outcomes and clinical characteristics. Stromal cells showed higher m1A scores, suggesting a regulatory role in the TME. There was a positive correlation between m1A-related gene expression and immune checkpoint genes. Moreover, the constructed prognostic model showed robust predictive performance and outperformed other recently published models.

The findings suggest that m1A-related genes are not only valuable biomarkers for CRC prognosis but also have significant implications for the immune landscape and could serve as potential targets for therapeutic intervention, particularly in the context of immunotherapy. For instance, SLC12A2 was found to enhance invasion, proliferation, and migration of colorectal cancer cells while inhibiting apoptosis. Further studies are needed to understand the functional roles of m1A modifications across different cell types within the TME.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy and a leading cause of cancer-related deaths globally. The asymptomatic progression of early-stage HCC often results in diagnosis at advanced stages, significantly limiting therapeutic options and worsening prognosis. Immunotherapy, with immune checkpoint inhibitors (ICIs) at the forefront, has revolutionized HCC treatment. Nevertheless, tumor heterogeneity, immune evasion, and the presence of immunosuppressive components within the tumor immune microenvironment (TIME) continue to compromise its efficacy. Furthermore, resistance or non-responsiveness to ICIs in some patients underscores the urgent need to unravel the complexities of the TIME and to design innovative strategies that enhance immunotherapeutic outcomes. Emerging evidence has revealed the pivotal role of N6-methyladenosine (m6A), a prominent RNA methylation modification, in shaping the TIME in HCC. By regulating RNA stability and translation, m6A influences immune-related factors, including cytokines and immune checkpoint molecules. This modification governs PD-L1 expression, facilitating immune escape and contributing to resistance against ICIs. Advances in this field have also identified m6A-related regulators as promising biomarkers for predicting immunotherapy response and as potential therapeutic targets for optimizing treatment efficacy. This review examines the regulatory mechanisms of m6A modification within the TIME of HCC, with a focus on its impact on immune cells and cytokine dynamics. It also explores the therapeutic potential of targeting m6A pathways to improve immunotherapy efficacy and outlines emerging directions for future research. These insights aim to provide a foundation for developing novel strategies to overcome immune resistance and advance HCC treatment.

The N6-methyladenosine binding protein YTHDF1, often upregulated in cancer, promotes tumor growth and hinders immune checkpoint blockade treatment. A comprehensive understanding of the molecular mechanisms governing YTHDF1 protein stability is pivotal for enhancing clinical response rates and the effectiveness of immune checkpoint blockade in cancer patients. Here, we report that USP5 interacts with YTHDF1, stabilizing it by removing K11-linked polyubiquitination. Insulin activates mTORC1, phosphorylating USP5 and promoting its dimerization, which binds to and protects YTHDF1 from degradation. Conversely, the CUL7-FBXW8 E3 ligase promotes YTHDF1 degradation. Deficiency in YTHDF1 or USP5 increases PD-L1 expression and suppresses immune-related gene expression, facilitating immune evasion. Combining USP5 inhibition with anti-PD-L1 therapy enhances anti-tumor immunity, suggesting USP5 as a potential biomarker for patient stratification. This study reveals a ubiquitination-dependent regulation of YTHDF1, proposing USP5 inhibition alongside PD-(L)1 blockade as a promising cancer treatment strategy.

Cellular aging is a multifactorial and intricately regulated physiological process with profound implications. The interaction between cellular senescence and cancer is complex and multifaceted, senescence can both promote and inhibit tumor progression through various mechanisms. M6A methylation modification regulates the aging process of cells and tissues by modulating senescence-related genes. In this review, we comprehensively discuss the characteristics of cellular senescence, the signaling pathways regulating senescence, the biomarkers of senescence, and the mechanisms of anti-senescence drugs. Notably, this review also delves into the complex interactions between senescence and cancer, emphasizing the dual role of the senescent microenvironment in tumor initiation, progression, and treatment. Finally, we thoroughly explore the function and mechanism of m6A methylation modification in cellular senescence, revealing its critical role in regulating gene expression and maintaining cellular homeostasis. In conclusion, this review provides a comprehensive perspective on the molecular mechanisms and biological significance of cellular senescence and offers new insights for the development of anti-senescence strategies.

Wilms tumor 1-associated protein (WTAP) plays a critical role in various cancers, including colorectal cancer (CRC). However, the biological function and molecular mechanisms of WTAP in CRC remain to be elucidated.

We determined the expression of WTAP and its correlation with unfavorable prognosis of CRC using RNA-seq and the UALCAN dataset. And we investigated the effects of WTAP on CRC cells using cell proliferation assay, colony formation, cell migration and invasion, and subcutaneous xenograft experiments. We then knockdown of WTAP to identify candidate targets of WTAP. Moreover, the mRNA stability of SRY-box transcription factor 1 (SOX1) was assessed by overexpressing YTHDF2. Finally, we investigated the regulatory mechanism of WTAP in CRC by MeRIP assay, RNA pulldown, dual-luciferase reporter assay, and RIP assay.

We demonstrated that CRC patients with a high expression of WTAP have a risk prognosis. Additionally, WTAP expression can serve as a predictor of survival in CRC. WTAP promoted the proliferation and tumor growth of CRC cells. Moreover, WTAP has been recognized as the upstream regulator of SOX1. WTAP regulated the m6A modification, resulting in the post-transcriptional inhibition of SOX1. YTHDF2 plays a role in promoting mRNA degradation. Then, SOX1 can hinder the progression of CRC. Furthermore, WTAP can regulate the proliferation, migration, and invasion of CRC cells by SOX1 via an m6A-YTHDF2-dependent manner.

Our findings demonstrate that WTAP-mediated m6A modification facilitated the progression of CRC through the YTHDF2-SOX1 axis and could serve as a potential therapeutic targeting for CRC.

Breast cancer is the most frequently diagnosed cancer among women worldwide with high morbidity and mortality. Previous studies have indicated that RNA-binding motif protein-15 (RBM15), an N6-methyladenosine (m6A) writer, is implicated in the growth of breast cancer cells. Herein, we aimed to explore the function and detailed mechanism of RBM15 in breast cancer.

In this research, UALCAN databases were applied to analyze the expression of RBM15 or Karyopherin-2 alpha (KPNA2) in BRCA. RBM15 and KPNA2 mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR) assay. RBM15, KPNA2, and Programmed cell death ligand 1 (PD-L1) protein levels were measured using western blot. Cell proliferation, migration, and invasion were assessed using 5-ethynyl-2'-deoxyuridine (EdU) and Transwell assays. The biological role of RBM15 on breast cancer tumor growth was verified using the xenograft tumor model in vivo. Effects of breast cancer cells on the proliferation and apoptosis of CD8+ T cells were analyzed using flow cytometry. Interaction between RBM15 and KPNA2 was validated using methylated RNA immunoprecipitation (MeRIP) and dual-luciferase reporter assays.

RBM15 and KPNA2 were highly expressed in breast cancer tissues and cell lines. Furthermore, RBM15 silencing might suppress breast cancer cell proliferation, migration, invasion, and lymphocyte immunity in vitro, as well as block tumor growth in vivo. At the molecular level, RBM15 might improve the stability and expression of KPNA2 mRNA via m6A methylation.

RBM15 might contribute to the malignant progression and immune escape of breast cancer cells partly by modulating the stability of KPNA2 mRNA, providing a promising therapeutic target for breast cancer.

N6-methylation is a modification in which a methyl group is added to the adenine base of a nucleotide. This modification is crucial for controlling important functions that are vital for gene expression, including mRNA splicing, stability, and translation. Due to its intricate participation in both normal cellular processes and the course of disease, as well as its critical role in determining cell fate, N6-methyladenosine (m6A) alteration has recently attracted a lot of interest. The formation and progression of many diseases, especially cancer, can be attributed to dysregulated m6A alteration, which can cause disturbances in a variety of cellular functions, such as immunological responses, cell proliferation, and differentiation. In this study, we examine how m6A dysregulation affects hepatocellular carcinoma (HCC), with a particular emphasis on how it contributes to immunological evasion and carcinogenesis. We also investigate its potential as a novel therapeutic target, providing new perspectives on potential therapeutic approaches meant to enhance clinical results for patients with HCC.

Fibroblast activation protein (FAP)-targeted radioligand therapy, with immunomodulatory effects, has shown efficacy in both preclinical and clinical studies. We recently reported on a novel dimeric FAP-targeting radiopharmaceutical, 68Ga/177Lu-DOTA-2P(FAPI)2, which demonstrated increased tumor uptake and prolonged retention in various cancers. However, further exploration is required to understand the therapeutic efficacy and underlying mechanisms of combining 68Ga/177Lu-DOTA-2P(FAPI)2 radioligand therapy with PD-1/PD-L1 immunotherapy.

Regarding the change in PD-L1 expression and DNA double-strand breaks induced by radiopharmaceuticals, CT26-FAP tumor cells were incubated with 68Ga and 177Lu labeled DOTA-2P(FAPI)2, respectively. Monotherapy with 68Ga-DOTA-2P(FAPI)2, 177Lu-DOTA-2P(FAPI)2, and PD-L1 immunotherapy as well as combination therapy (68Ga/177Lu-DOTA-2P(FAPI)2 and PD-L1 immunotherapy) were tested and evaluated to evaluate in vivo antitumor efficacy. Furthermore, immunohistochemical staining and single-cell RNA sequencing were used to analyze changes in the tumor microenvironment (TME) and elucidate the underlying mechanisms of action of this combination therapy.

Our findings indicated that FAP-targeting radiopharmaceuticals can induce DNA double-strand breaks and upregulate PD-L1 expression, with 177Lu-DOTA-2P(FAPI)2 proving to be more effective than 68Ga-DOTA-2P(FAPI)2. Both 68Ga-DOTA-2P(FAPI)2 and 177Lu-DOTA-2P(FAPI)2 radiopharmaceuticals significantly improved therapeutic outcomes when combined with anti-PD-L1 monoclonal antibody (αPD-L1 mAb). Notably, the combination of 177Lu-DOTA-2P(FAPI)2 with αPD-L1 mAb immunotherapy eliminated tumors in mouse models. Mice treated with this regimen not only exhibited exceptional responses to the initial immune checkpoint inhibitor therapy but also showed 100% tumor rejection on subsequent tumor cell re-inoculation. Further mechanistic studies have shown that 177Lu-DOTA-2P(FAPI)2 combined with αPD-L1 mAb can reprogram the TME, enhancing antitumor intercellular communication, which activates antitumor-related intercellular contacts such as FasL-Fas interactions between T cells and NK cells with tumor cells and increasing the proportion of infiltrating CD8+ T-cells while reducing regulatory T cells and inhibiting tumor progression. Our research also demonstrates that mature neutrophils play a role in enhancing the efficacy of the combined therapy, as shown in neutrophil-blocking experiments.

Our study robustly advocates for use of FAP-targeting radiopharmaceuticals, particularly 177Lu-DOTA-2P(FAPI)2, alongside immunotherapy in treating FAP-positive tumors. This combination therapy transforms the TME and enables a translatable approach to increasing the sensitivity to PD-1/PD-L1 immunotherapy, leading to improved complete remission rates and extended overall survival.

Osteosarcoma is a highly aggressive malignant bone tumor prone to metastasis, and its metastatic process is one of the main reasons for treatment failure and poor prognosis. Recent studies have demonstrated that modification of m6A methylation plays an important role in osteosarcoma metastasis, influencing both invasion and metastasis through various signaling pathways. Therefore, clarification of the specific effects of m6A methylation modification in osteosarcoma may reveal ways to improve the prognosis of osteosarcoma patients. The roles of various components involved in the m6A methylation modification process in osteosarcoma have been investigated, with studies focusing more on their effects than on their mechanisms. In this review, we focus on the interactions between the "writers," "erasers," and "readers" of m6A methylation and tumor metastasis-related factors to enhance the understanding of osteosarcoma and m6A methylation modification, with the aim of identifying clinical diagnostic biomarkers and potential therapeutic targets for osteosarcoma metastasis.

Colorectal cancer (CRC) is the third most common cancer type and the second highest mortality rate among cancers. However, the mechanisms underlying CRC progression remain to be fully understood. In this work, a recently identified m6A-modified RNA reader protein Proline-rich Coiled-coil 2a (PRRC2A) is markedly upregulated in CRC, and intestinal epithelium-specific deletion of Prrc2a significantly suppressed tumor cell growth, stemness, and migratory capacity, while its overexpression promoted these behaviors. Through multiomics analysis, PRRC2A directly targeted CSNK1E (encoding CK1ε), maintaining its RNA stability in an m6A-dependent manner, and that elevated CK1ε can concomitantly result in activation of the WNT and YAP signaling pathways. Interestingly, PRRC2A is directly regulated by the transcription factor ATF1 in its promoter. In summary, the work reveals a novel mechanism by which m6A reader PRRC2A promotes colorectal cancer progression via CK1ε and aberrant upregulation of WNT and YAP signaling. Therefore, PRRC2A and CK1ε can be potential therapeutic targets for treating CRC.

Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon-γ (IFN-γ) signaling, in which IFN-γ is linked to improved responsiveness to ICIs. Herein, the roles of RNA N6-methyladenosine (m6A) modifications in regulation of IFN-γ signaling and the responsiveness to ICIs are unveiled. The m6A-binding protein YTH N6-methyladenosine RNA-binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN-γ in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN-γ responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN-γ signaling, leading to reduced RNA stability and consequent downregulation of IFN-γ signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor-infiltrating lymphocytes, which are attributed to the augmentation of IFN-γ signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN-γ signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy.

N6-methyladenosine is one of the most common and reversible post-transcriptional modifications in eukaryotes, and it is involved in alternative splicing and RNA transcription, degradation, and translation. It is well known that cancer cells acquire energy through metabolic reprogramming to exhibit various biological behaviors. Moreover, numerous studies have demonstrated that m6A induces cancer metabolic reprogramming by regulating the expression of core metabolic genes or by activating metabolic signaling pathways. Meanwhile, m6A modifications and related regulators are key targets in the regulation of immune effects. We further summarize how m6A modifications contribute to tumor metabolism, and how these events affect the tumor immune microenvironment, with a specific focus on different cell types. Finally, we focus on the specific applications of this field to tumor immunotherapy. We review the potential role of m6A in metabolic reprogramming of tumor immune microenvironment and its regulatory mechanism, with the aim of providing new targets for tumor metabolic regulation and immunotherapy.

Most Colorectal Cancer (CRC) patients exhibit limited responsiveness to anti-programmed cell death protein 1 (PD-1) therapy, with the underlying mechanisms remaining elusive. Circular RNAs (circRNAs) play a significant role in tumorigenesis and development, with potential applications in tumor screening and predicting treatment efficacy. However, there are few studies exploring the role of circRNAs in CRC immune evasion.

circRNA microarrays were used to identify circPHLPP2. RT-qPCR was used to examine the associations between the expression level of circPHLPP2 and the clinical characteristics of CRC patients. MTS assay, clone formation experiment, subcutaneous tumor implantation and multicolor flow cytometry were used to confirm the biological function of circPHLPP2. RAN-seq, RT-qPCR, and WB experiments were performed to investigate the downstream signaling pathways involved in circPHLPP2. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to identify the proteins associated with circPHLPP2.

circPHLPP2 is up-regulated in CRC patients who exhibit resistance to anti-PD-1 based therapy. circPHLPP2 significantly promotes the proliferation and tumor growth of CRC cells. Knockdown of circPhlpp2 enhances the efficacy of anti-PD-1 in vivo. Mechanistically, the specific interaction between circPHLPP2 and ILF3 facilitates the nuclear accumulation of ILF3, which subsequently enhances the transcription of IL36γ. This process reduces NK cell infiltration and impairs NK cells' granzyme B and IFN-γ production, thereby promoting tumor progression.

Overall, our findings reveal a novel mechanism by which circRNA regulates CRC immune evasion. circPHLPP2 may serve as a prognostic biomarker and potential therapeutic target for CRC patients.

To determine the role of N6-methyladenosine (m6A) modification in the tumor immune microenvironment (TIME), as well as their association with lung adenocarcinoma (LUAD).