Glutamate is well-known as metabolite for maintaining the energy and redox homeostasis in cancer, moreover it is also the primary excitatory neurotransmitter in the central nervous system. However, whether glutamatergic signaling can regulate hepatocellular carcinoma (HCC) progression and the specific regulatory mechanisms are unknown. In the present study, we found that glutamate and its receptor NMDAR2B were significantly elevated in HCC patients, which predicts poor prognosis. Glutamate could upregulate CCL2 expression on hepatoma cells and further enhance the capability of tumor cells to recruit tumor-associated macrophages (TAMs). Mechanistically, glutamate could facilitate CCL2 expression through NMDAR pathway by decreasing the expression of EZH2, which regulates the H3K27me3 levels on the CCL2 promoter, rather than affecting DNA methylation. Moreover, inhibiting glutamate pathway with MK801 could significantly delay tumor growth, with reduced TAMs in implanted Hepa1-6 mouse HCC models. Our work suggested that glutamate could induce CCL2 expression to promote TAM infiltration by negatively regulating EZH2 levels in hepatoma cells, which might serve as a potential prognostic marker and a therapeutic target for HCC patients.

Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis is often late as current screening methods have limited sensitivity for early HCC. Moreover, current treatment regimens for intermediate-to-advanced HCC have high resistance rates, no robust predictive biomarkers, and limited survival benefits. A deeper understanding of the molecular biology of HCC may enhance tumor characterization and targeting of key carcinogenic signatures. The epigenetic landscape of HCC includes complex hallmarks of 1) global DNA hypomethylation of oncogenes and hypermethylation of tumor suppressors; 2) histone modifications, altering chromatin accessibility to upregulate oncogene expression, and/or suppress tumor suppressor gene expression; 3) genome-wide rearrangement of chromatin loops facilitating distal enhancer-promoter oncogenic interactions; and 4) RNA regulation via translational repression by microRNAs (miRNAs) and RNA modifications. Additionally, it is useful to consider etiology-specific epigenetic aberrancies, especially in viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are the main risk factors of HCC. This article comprehensively explores the epigenetic signatures in HCC, highlighting their potential as biomarkers and therapeutic targets. Additionally, we examine how etiology-specific epigenetic patterns and the integration of epigenetic therapies with immunotherapy could advance personalized HCC treatment strategies.

Immune checkpoint inhibitors (ICIs) have revolutionized colon cancer treatment, but their efficacy is largely restricted by the limited presence of CD8+ cytotoxic T lymphocytes (CTLs). However, the specific genetic alterations that impact the CD8+ CTL infiltration in colon cancer remain poorly understood. Here, we analyzed clinical and multi-omics data from the Memorial Sloan-Kettering Cancer Center (MSKCC) ICIs-treated and The Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) cohorts to screen the key mutations that may influence the efficacy of immunotherapy. We found that patients with NCOA3 mutations exhibit better response to immunotherapy and higher CD8+ CTL infiltration. In vitro and in vivo experiments revealed that mutant NCOA3 increases the efficacy of anti-PD-L1 and CD8+ CTL recruitment by upregulating C-X-C motif chemokine ligand 9 (CXCL9), which is dependent on its impaired intrinsic histone acetyltransferase activity. Mechanistically, wild-type NCOA3 as histone acetyltransferase upregulates Heat shock protein 90 alpha (HSP90α) by enhancing histone H3 lysine 27 acetylation (H3K27ac) at its promoter region. Increased HSP90α stabilizes Enhancer of zeste homolog 2 (EZH2), which then increase the histone H3 lysine 27 trimethylation (H3K27me3) at the CXCL9 promoter region, thereby suppressing the expression of CXCL9. Targeted inhibition of NCOA3 by small molecular inhibitor SI-2 improves the efficacy of PD-L1 blockade therapy. NCOA3 could serve as a novel biomarker and potential target to improve the efficacy of immunotherapy.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited targeted therapies and high recurrence rates. While immune checkpoint inhibitors (ICIs) have shown promise, their efficacy as monotherapy is limited. Clinically, ICIs demonstrate significant benefit primarily when combined with chemotherapy, particularly in the neoadjuvant setting for early-stage TNBC, which yields superior outcomes compared to adjuvant therapy. This review elucidates the tumor immunological principles underlying these observations. We discussed how the suppressive tumor microenvironment (TME), progressive T cell exhaustion, and associated epigenetic scarring constrain ICI monotherapy effectiveness. Crucially, we highlight the immunological advantages of the neoadjuvant approach: the presence of the primary tumor provides abundant antigens, and intact tumor-draining lymph nodes (TDLNs) act as critical sites for ICI-mediated priming and expansion of naïve and precursor exhausted T cells. This robust activation within TDLNs enhances systemic anti-tumor immunity and expands the T cell repertoire, a process less effectively achieved in the adjuvant setting after tumor resection. These mechanisms provide a strong rationale for the improved pathological complete response (pCR) rates and event-free survival observed with neoadjuvant chemoimmunotherapy, as demonstrated in trials like KEYNOTE-522. We further explore the implications for adjuvant therapy decisions based on treatment response, the challenges of ICI resistance, the need for predictive biomarkers, management of immune-related adverse events (irAEs), and future therapeutic directions. Understanding the dynamic interplay between chemotherapy, ICIs, T cells, and the TME, particularly the role of TDLNs in the neoadjuvant context, is essential for optimizing immunotherapy strategies and improving outcomes for patients with TNBC.

CNS tumors are the leading cause of cancer-related death in children, highlighting the dire need for new treatment strategies. CAR T cells represent a unique approach, distinct from the cytotoxic chemotherapies and small-molecule inhibitors that have dominated the clinical trial space for decades. Phase I CAR T-cell trials have shown feasibility and possible efficacy against pediatric CNS tumors; however, many challenges must be overcome if these therapeutics are going to be beneficial to most affected children. Although rapid translational development and early-phase trials have quickly evolved our understanding, the pediatric CNS CAR T-cell community now yearns for critical assessments and open dialogue about overcoming the remaining obstacles ahead.

Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) link to unfavourable prognoses. We explored the mechanism of enhancer of zeste homologue 2/histone H3 of lysine 27 (EZH2/H3K27me3) downregulating C-X-C motif chemokine 10 (CXCL10) to affect CD8+ T-cell exhaustion, participating in MDS-to-AML transformation. NHD13 mice were treated with GSK126 (EZH2 inhibitor) and CXCL10 neutralizing antibody, with transformation time, blood cell counts and CD8+ T cell determined. SKM-1 cells treated with short hairpin-EZH2, overexpressing-EZH2, GSK126 and CXCL10 were co-cultured with CD8+ T cells. EZH2, CXCL10, H3K27me3 and EZH2 levels and EZH2 enzyme activity were assessed. CD8+ T-cell cytotoxicity, exhaustion, apoptosis and SKM-1 cell malignant behaviours were evaluated. In vivo, EZH2 inhibition upregulated CXCL10, decelerating MDS to AML transformation and delaying CD8+ T-cell exhaustion. EZH2 inhibition elevated peripheral blood cells, alleviated splenomegaly, reduced CD8+ T cells, elevated CD8+ T cytotoxicity and abated CD8+ T-cell exhaustion in NHD13 mice. CXCL10 neutralizing antibody accelerated AML transformation by inhibiting CD8+ T-cell exhaustion via EZH2. In vitro, EZH2 overexpression facilitated CD8+ T-cell exhaustion and SKM-1 cell malignant behaviours. EZH2-mediated H3K27me3 curbed CXCL10 transcription and secretion. Collectively, EZH2/H3K27me3 downregulates CXCL10 to facilitate CD8+ T-cell exhaustion, accelerating transformation from MDS to AML.

Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and the tumour microenvironment (TME), including immune cells, stromal components, and extracellular matrix proteins. The epithelial-mesenchymal transition (EMT) plays a crucial role in providing cancer cells with invasive and stem-like properties, promoting dissemination and resistance to apoptosis. Conversely, the mesenchymal-epithelial transition (MET) facilitates metastatic colonisation and tumour re-initiation. Immune cells within the TME contribute to either anti-tumour response or immune evasion. These cells secrete cytokines, chemokines, and growth factors that shape the immune landscape and influence responses to immunotherapy. Notably, immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often dictated by the immune composition of the tumour site. Elucidating the molecular cross-talk between immune and cancer cells, identifying predictive biomarkers for ICB response, and developing strategies to convert cold tumours into immune-active environments is critical to overcoming resistance to immunotherapy and improving patient survival.

Enhancer of zeste homolog 2 (EZH2) is highly expressed in triple-negative breast cancer (TNBC) and induces massive histone modification via trimethylation at lysine 27 of histone H3 (H3K27me3). The expression level of programmed death ligand 1 (PD-L1) is crucial for determining the indications for immune checkpoint inhibitors in patients with TNBC. This study aimed to clarify the regulatory roles of EZH2 and H3K27me3 in the PD-L1 expression in TNBC cells.

The change in the expression of PD-L1 at mRNA and protein levels was investigated by establishing an EZH2-knockdown MDA-MB-231 cell line using siRNA followed by RT-qPCR and western blotting analyses. Localization of the PD-L1 protein was assessed using immunofluorescence. Chromatin immunoprecipitation (ChIP) assays were performed to investigate the histone methylation status of PD-L1 promoter regions. The correlation among PD-L1, EZH2, and H3K27me3 protein expressions was explored in 57 patients with TNBC through immunohistochemistry.

Knockdown of EZH2 restored the PD-L1 expression and localization of PD-L1 protein in the cellular membrane. ChIP assay revealed that the knockdown of EZH2 diminished H3K27 trimethylation and enhanced H3K4 trimethylation in the promoter region of PD-L1. Immunohistochemical analysis of TNBC specimens reflected an inverse correlation between PD-L1 expression and H3K27me3 nuclear positivity; however, no correlation between H3K27me3 status and EZH2 expression was observed.

The downregulation of EZH2 can potentially enhance the efficacy of immune checkpoint inhibitors in patients with TNBC and may provide a new therapeutic strategy.

Despite advances in cancer immunotherapy, colorectal cancer patients exhibit limited therapeutic responses. Therefore, the exploration of strategies combining immunotherapy with adjuvant approaches to enhance adaptive immune responses is in demand. Here, we perform a customized in vivo CRISPR-Cas9 screen to target genes encoding membrane and secreted proteins in CRC mouse models with different immune characteristics. We observe that loss of membrane-bound transcription factor site-1 protease (MBTPS1) in tumor cells enhances antitumor immunity and potentiates anti-PD-1 therapy. Mechanistic studies reveal that tumor cell-intrinsic MBTPS1 competes with USP13 for binding to STAT1, thereby disrupting the USP13-dependent deubiquitination-mediated STAT1 stabilization. The upregulated STAT1-transcribed chemokines including CXCL9, CXCL10, and CXCL11, promote CXCR3+CD8+ T cell infiltration. Notably, the regulatory role of MBTPS1 in antitumor immunity operates independently of its classic function in cleaving membrane-bound transcription factors. Collectively, our results provide a theoretical basis for MBTPS1 as a potential immunotherapy target.

Over the past few years, immune checkpoint inhibitors resulted in magnificent and durable successes in treating cancer; however, only a minority of patients respond favorably to the treatment due to a broad-spectrum of tumor-intrinsic and tumor-extrinsic factors. With the recent insights gained into the mechanisms of resistance, combination treatment strategies to overcome the resistance and enhance the therapeutic potential of immune checkpoint inhibitors are emerging and showing promising results in both pre-clinical and clinical settings. This has been derived through multiple interconnected mechanisms such as enhancing tumor immunogenicity, improving neoantigen processing and presentation in addition to augmenting T cell infiltration and cytotoxic potentials. In the clinical settings, several avenues of combination treatments involving immune checkpoint inhibitors were associated with considerable improvement in the therapeutic outcome in terms of patient's survival and tumor growth control. This, in turn, increased the spectrum of cancer patients benefiting from the unprecedented and durable effects of immune checkpoint inhibitors leading to their adoption as a first-line treatment for certain cancers. Moreover, the significance of precision medicine in cancer immunotherapy and the unmet demand to develop more personalized predictive biomarkers and treatment strategies are also highlighted in this review.

CXCR3 is a chemokine receptor for three ligands: CXCL9, CXCL10, and CXCL11. Accumulating evidence, including data presented here, suggests that the interaction between CXCL9/CXCL10 and CXCR3 not only attracts CXCR3+ T cells but also promotes the induction of IFNγ-high effector/cytotoxic CD4+ and CD8+ T cells, establishing a CXCL9/10-CXCR3-IFNγ self-amplifying cycle that promotes efficient cancer cell killing. One of the homeostatic mechanisms that may limit this cycle is the cleavage of the two N-terminal amino acids of these chemokines by Dipeptidyl Peptidase IV (DPP-4). The modified chemokines retain their ability to bind CXCR3 but no longer activate it, becoming competitive antagonists to native CXCL9/CXCL10. To develop a DPP-4-resistant variant, we combined biochemical analysis with computational modeling, demonstrating that the addition of N-terminal glutamine (Q) to CXCL9-Fc and CXCL10-Fc rendered them fully active CXCR3 agonists, yet resistant to DPP-4 cleavage. Preclinical evaluations imply that they offer significant therapeutic potential in cancer immunotherapy.

Most molecular classifications of cancer are based on bulk-tissue profiles that measure an average over many distinct cell types. As such, cancer subtypes inferred from transcriptomic or epigenetic data are strongly influenced by cell-type composition and do not necessarily reflect subtypes defined by cell-type-specific cancer-associated alterations, which could lead to suboptimal cancer classifications.

To address this problem, we here propose the novel concept of cell-type-specific combinatorial clustering (CELTYC), which aims to group cancer samples by the molecular alterations they display in specific cell types. We illustrate this concept in the context of DNA methylation data of liver and kidney cancer, deriving in each case novel cancer subtypes and assessing their prognostic relevance against current state-of-the-art prognostic models.

In both liver and kidney cancer, we reveal improved cell-type-specific prognostic models, not discoverable using standard methods. In the case of kidney cancer, we show how combinatorial indexing of epithelial and immune-cell clusters define improved prognostic models driven by synergy of high mitotic age and altered cytokine signaling. We validate the improved prognostic models in independent datasets and identify underlying cytokine-immune-cell signatures driving poor outcome.

In summary, cell-type-specific combinatorial clustering is a valuable strategy to help dissect and improve current prognostic classifications of cancer in terms of the underlying cell-type-specific epigenetic and transcriptomic alterations.

In EGFR-mutated lung adenocarcinoma (EGFRm LUAD), EGFR mutations do not necessarily result in increased EGFR expression (EGFR-exp), which differs among patients. However, the factors influencing EGFR-exp and the impact of EGFR-exp on tumor characteristics in patients with EGFRm LUAD remain unclear.

Whole-exome and RNA sequencing were performed for patients with early- and advanced-stage EGFRm LUAD. The patients were classified into low or high EGFR-exp groups based on the median transcripts per million. We retrospectively examined the association between EGFR-exp, genomic characteristics, downstream EGFR signaling activity, tumor microenvironment (TME) status, and clinical outcomes.

This study included 450 and 45 patients in the early- and advanced-stage cohorts, respectively. In both cohorts, the EGFR-exp low group exhibited a lower incidence of TP53 co-mutations and EGFR amplification and a higher incidence of EGFR subclonal mutations than the EGFR-exp high group. Furthermore, downstream EGFR signaling pathways, such as the MAPK signaling, were less activated in the EGFR-exp low group. However, this group showed significantly enriched adaptive immune response pathways (Q < 0.0001) and an immune-inflamed TME. Additionally, a low EGFR-exp was a significantly favorable factor for postoperative relapse (odds ratio [OR], 0.6; P = 0.04). However, in the advanced-stage cohort, a low EGFR-exp was a significant risk factor for non-responders to osimertinib (OR, 17.5; P = 0.03).

In EGFRm LUAD, significant associations were observed between EGFR-exp levels and both EGFR signaling pathways and adaptive immune status, which in turn influence clinical outcomes. This large-scale multi-omics analysis highlights the heterogeneity among patients with EGFRm LUAD and emphasizes the need to assess EGFR-exp levels alongside mutation status for optimal treatment strategies in EGFRm LUAD.

Immune checkpoint inhibitors (ICIs) redefined the therapeutics of non-small cell lung cancer (NSCLC), leading to significant survival benefits and unprecedented durable responses. However, the majority of the patients develop resistance to ICIs, either primary or acquired. Establishing a definition of primary resistance to ICIs in different clinical scenarios is challenging and remains a work in progress due to the changing landscape of ICI-based regimens, mainly in the setting of early-stage NSCLC. The mechanisms of primary resistance to ICIs in patients with NSCLC include a plethora of pathways involving a cross-talk of the tumor cells, the tumor microenvironment and the host, leading to the development of an immunosuppressive phenotype. The optimal management of patients with NSCLC following primary resistance to ICIs represents a significant challenge in current thoracic oncology. Research in this field includes exploring other immunotherapeutic approaches, such as cancer vaccines, and investigating novel antibody-drug conjugates in patients with NSCLC.

The emergence of molecularly targeted therapies and immunotherapies has revolutionized cancer treatment, yet the optimal sequencing of these modalities remains debated. While targeted therapies often induce initial immunostimulatory effects, the development of resistance is accompanied by dynamic alterations in the tumor-immune microenvironment. These changes can promote tumor growth, hinder immune surveillance, and contribute to subsequent immunotherapy resistance. This review focuses on solid tumors and summarizes the immunomodulatory effects arising in the context of targeted therapy resistance, highlighting the challenges they pose for the subsequent immunotherapy efficacy.

Immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here we leverage genetic mouse models, single-cell sequencing and cell depletion studies to show that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2+ macrophages and subsequent recruitment of effector memory CD8+ T cells. We identify a positive feedback loop between CCR2+ macrophages (positive for the chemokine receptor CCR2) and CD8+ T cells driven by IL-12b, TNF and IFNγ signaling that promotes myocardial inflammation and show that previous exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates left ventricular remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.

The process of tumor development involves tumor cells eluding detection and suppression of immune responses, which can cause decreased tumor cell antigenicity, expression of immunosuppressive molecules, and immunosuppressive cell recruitment to the tumor microenvironment (TME). Immunologically and genomically integrated analysis (immunogenomic analysis) of patient specimens has revealed that oncogenic aberrant signaling is involved in both carcinogenesis and immune evasion. In noninflamed cancers such as epidermal growth factor receptor (EGFR)-mutated lung cancers, genetic abnormalities in cancer cells contribute to the formation of an immunosuppressive TME by recruiting immunosuppressive cells, which cannot be fully explained by the cancer immunoediting hypothesis. This review summarizes the latest findings regarding the links between cancer genetic abnormalities and immunosuppression causing clinical resistance to immunotherapy. We propose the concepts of immunogenomic cancer evolution, in which cancer cell genomic evolution shapes the immunosuppressive TME, and immunogenomic precision medicine, in which cancer immunotherapy can be combined with molecularly targeted reagents that modulate the immunosuppressive TME.

Immunogenic cell death (ICD), a type of regulatory cell death, plays an important role in activating the adaptive immune response. Activation of the tumor-specific immune response is accompanied by the cell surface exposure of calreticulin and heat-shock proteins, the secretion of adenosine triphosphate, and the release of high mobility group box-1. In this review, we summarize and classify the latest types of ICD inducers and their molecular mechanisms, and discuss the effects and potential applications of inducing ICD by chemotherapy drugs, targeted drugs, and oncolytic viruses in clinical research. We also explore the potential role of epigenetic modifiers in the induction of ICD, and clarify the synergistic anti-tumor effects of nano-pulse stimulation, radiosensitizers for radiotherapy, photosensitizers for photodynamic therapy, photothermal therapy, and other physical stimulation, combined with radiotherapy and chemotherapy induced-ICD, in multimodal immunotherapy. In addition, we elucidate the molecular mechanism of ICD in detail, including the calcium imbalance, mitochondrial stress, and the interactions in the tumor microenvironment. Ultimately, this review aims to offer deeper insight into the factors and mechanisms of ICD induction and provide a theoretical basis for the future development of ICD-based immunotherapy.

Immunotherapy, particularly immune checkpoint inhibitor therapy, has demonstrated clinical benefits in solid tumours. Despite its satisfactory clinical efficacy, it still faces several issues, such as limited eligibility, low response rates and cytotoxicity. Cancer epigenetics implies that tumour cells exhibit unique phenotypes because of their unique characteristics, thus reprogramming of the epigenome holds promise for cancer therapy. Epigenetic regulation plays an important role in regulating gene expression during tumour development and maintenance. Epigenetic regulators induce cancer cell cycle arrest, apoptosis and differentiation of cancer cells, thereby exerting anti-tumour effects. Recent studies have revealed a significant correlation between epigenetic regulatory factors and immune checkpoint therapy. Epigenetics can modulate various aspects of the tumour immune microenvironment and immune response to enhance the sensitivity of immunotherapy, such as lowering the concentration required and mitigating cytotoxicity. This review primarily discusses DNA methyltransferase inhibitors, histone deacetylase inhibitors, enhancer of zeste homolog 2 inhibitors and lysine-specific demethylase 1 inhibitors, which are associated with transcriptional repression. This repression alters the expression of genes involved in the immune checkpoint, thereby enhancing the effectiveness of immunotherapy. We also discuss the potential and challenges of tumour immunotherapy and highlight its advantages, application challenges and clinical research on integrating epigenetic regulatory factors with tumour immunotherapy.

Tumor resistance to chimeric antigen receptor T cell (CAR-T) and, in general, to adoptive cell immunotherapies (ACTs) is a major challenge in the clinic. We hypothesized that inhibiting the tumor drivers' methyltransferases EZH2 and EZH1 could enhance ACT by rewiring cancer cells to a more immunogenic state. In human B cell lymphoma, EZH2 inhibition (tazemetostat) improved the efficacy of anti-CD19 CAR-T by enhancing activation, expansion, and tumor infiltration. Mechanistically, tazemetostat-treated tumors showed upregulation of genes related to adhesion, B cell activation, and inflammatory responses, and increased avidity to CAR-T. Furthermore, tazemetostat improved CAR- and TCR-engineered T cell efficacy in multiple liquid (myeloma and acute myeloid leukemia) and solid (sarcoma, ovarian, and prostate) cancers. Lastly, combined EZH1/EZH2 inhibition (valemetostat) further boosted CAR-T efficacy and expansion in multiple cancers. This study shows that EZH1/2 inhibition reprograms tumors to a more immunogenic state and potentiates ACT in preclinical models of both liquid and solid cancers.

Polycomb Repressive Complex 2 (PRC2) is a central regulator of gene expression via the trimethylation of histone H3 on lysine 27. This epigenetic modification plays a crucial role in maintaining cell identity and controlling differentiation, while its dysregulation is closely linked to cancer progression. PRC2 silences tumor suppressor genes, promoting cell proliferation, metastasis, epithelial-mesenchymal transition, and cancer stem cell plasticity. Enhancement of zeste homolog 2 (EZH2) overexpression or gain-of-function mutations have been observed in several cancers, including lymphoma, breast, and prostate cancers, driving aggressive tumor behavior and drug resistance. In addition to EZH2, other PRC2 components, such as embryonic ectoderm development (EED) and suppressor of zeste 12, are essential for complex stability and function. EED, in particular, enhances EZH2 activity and has emerged as a therapeutic target. Inhibitors like MAK683 and EED226 disrupt EED's ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components. PRC2's role extends beyond gene repression, as it contributes to metabolic reprogramming in tumors, regulating glycolysis and lipid synthesis to fuel cancer growth. Furthermore, PRC2 is implicated in chemoresistance, particularly by modulating DNA damage response and immune evasion. Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2's multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their use in combination with standard chemotherapy or immunotherapy has great potential for improving patient outcomes in cancers driven by PRC2 dysregulation.

Targeting the dysregulation of epigenetic mechanisms in cancer has emerged as a promising therapeutic strategy. Although the significant rationale progress of epigenetic therapies in blocking cancer cells, how epigenetic regulation shapes tumor microenvironment (TME) and establishes antitumor immunity remains less understood. Recent study focus has been put on the epigenetic-mediated changes in the fate of immune cells, including the differentiation, expansion, recruitment, functionalization, and exhaustion of T cells, natural killer (NK) cells, tumor-associated macrophages (TAMs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and B cells within the TME. Here, we review the latest molecular and clinical insights into how DNA modifications, histone modification, and epitranscriptome-related regulations shape immune cells of various cancers. We also discuss opportunities for leveraging epigenetic therapies to improve cancer immunotherapies. This review provides the epigenetic foundations of cancer immunity and proposes the future direction of combination therapies.

Inflammation is a multifaceted defense mechanism of the immune system against infection. Chronic inflammation is intricately linked to all stages of tumorigenesis and is therefore associated with an elevated risk of developing serious cancers. Epigenetic mechanisms have the capacity to trigger inflammation as well as facilitate tumor development and transformation within an inflammatory context. They achieve this by dynamically modulating the expression of both pro-inflammatory and anti-inflammatory cytokines, which in turn sustains chronic inflammation. The aberrant epigenetic landscape reconfigures the transcriptional programs of inflammatory and oncogenic genes. This reconfiguration is pivotal in dictating the biological functions of both tumor cells and immune cells. Aberrant histone H3 lysine 27 site (H3K27) methylation has been shown to be involved in biological behaviors such as inflammation development, tumor progression, and immune response. The establishment and maintenance of this repressive epigenetic mark is dependent on the involvement of the responsible histone modifying enzymes enhancer of zeste homologue 2 (EZH2), jumonji domain containing 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat gene X (UTX) as well as multiple cofactors. In addition, specific pharmacological agents have been shown to modulate H3K27 methylation levels, thereby modulating inflammation and carcinogenesis. This review comprehensively summarises the current characteristics and clinical significance of epigenetic regulation of H3K27 methylation in the context of inflammatory response and tumor progression.

Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].

In cutaneous melanoma, epigenetic dysregulation is implicated in drug resistance and tumor immune escape. However, the epigenetic mechanisms that influence immune escape remain poorly understood. To elucidate how epigenetic dysregulation alters the expression of surface proteins that may be involved in drug targeting and immune escape, we performed a 3-dimensional surfaceome screen in primary melanoma cultures and identified the DNA-methyltransferase inhibitor decitabine as significantly upregulating the costimulatory molecule ICAM-1. By analyzing The Cancer Genome Atlas melanoma dataset, we further propose ICAM-1 upregulation on melanoma cells as a biomarker of a proinflammatory and antitumorigenic signature. Specifically, we showed that DNA-methyltransferase inhibitor administration upregulated the expression of the antigen-presenting machinery, HLA class I/II, as well as the secretion of the proinflammatory chemokines CXCL9 and CXCL10. Our in silico analysis on The Cancer Genome Atlas and ex vivo experiments on human primary melanoma samples revealed that increased ICAM-1 expression positively correlated with increased immunogenicity of human melanoma cells and correlated with increased immune cell infiltration. These findings suggest a therapeutic approach to modulate the immunogenic phenotype of melanoma cells, hence supporting the exploration of DNA-methyltransferase inhibitor as a potential inducer of infiltration in immunologically cold tumors.

In recent years, researchers have been paying special attention to the tumor microenvironment (TME). One of the most important factors contributing to the development and progression of cancer is the destruction of elements of the extracellular matrix (ECM). The most important substances involved in regulating the extracellular matrix degradation process are extracellular matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). In the process of cancer cell migration, chemokines secreted by target tissues, as well as the profile of chemokine receptors presented on cancer cells, play a key role. In the presented work, five components of the TME were selected: MMP-2, MMP-7, TIMP-2, CXCL-9, and CXCL-10. In the years 2018-2021, peripheral blood samples were collected before the start of treatment and then on day 33 of intensive treatment from 31 patients diagnosed with ALL. The results indicate that the levels of MMP-2, MMP-7, and TIMP-2 did not statistically significantly change before and during treatment of ALL patients. The decrease in CXCL-9 and CXCL-10 levels in the patients' serum on the 33rd day of therapy turned out to be statistically significant. Our study indicates that serum is also a valuable material for the evaluation of these substances. Conclusions: CXCL-9 and CXCL-10 could be used as one of markers for monitoring the response to treatment and a potential marker of ALL recurrence in pediatric patients. The role of MMP-2, MMP-7, and TIMP-2 in the assessment of response to therapy in children with ALL has not been confirmed.

Colorectal precancers in Lynch syndrome (LS) exhibit a distinct immune profile, presenting unique opportunities for developing immune-interception strategies to prevent carcinogenesis. Epigenetic modulation by EZH2 of immune-related genes is implicated in the carcinogenesis of different cancer types, including colorectal cancer. This study utilizes a mouse model of LS and ex vivo colonic organoids to assess the effects of the EZH2 inhibitor GSK503 on immune regulatory pathways, tumorigenesis, and epigenetic reprogramming. Our findings revealed that GSK503 significantly increased CD4+ and CD8+ T cells in both splenocytes and colonic mucosa of treated mice compared with controls. Additionally, a preventive dose of GSK503 over 9 weeks notably reduced adenoma multiplicity, demonstrating its efficacy as a preventive modality. Single-cell RNA-Seq and molecular analyses showed activation of immune and apoptotic markers, along with a reduction in H3K27 methylation levels in colonic crypts. ChIP sequencing further revealed decreased levels of H3K27me3 and H3K4me1, while levels of the active enhancer marks H3K4me3 and H3K27Ac increased in treated mice. Collectively, these findings indicate that EZH2 inhibition enhances immune responses through epigenetic reprogramming in the genome of LS mice, establishing a promising framework for the clinical development of EZH2 inhibitors as a cancer prevention strategy for LS carriers.

Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in patients with non-small cell lung cancer (NSCLC) lacking targetable oncogenic alterations. However, their efficacy in individuals with such genomic alterations remains heterogeneous and poorly understood. In detail, certain oncogenic alterations in TP53, EGFR (uncommon mutations), KRAS (G12C), BRAF (non-V600E), MET (amplifications), FGFR1 and FGFR4, actively modify MAPK, PI3K, and STING signaling, thus remodeling tumoral immune phenotype and are associated with high TMB counts, enriched T lymphocyte tumor infiltration, and high expression of antigen-presenting molecules, supporting their consideration as part of the eligibility criteria for ICIs treatment. Nonetheless, other oncogenic alterations are associated with an immunosuppressive TME, low TMB counts, and downregulation of targetable immune checkpoints, in which novel therapeutic approaches are currently being tested to overcome their intrinsic resistance. In this context, this review discusses the fundamental mechanisms by which frequent driver alterations affect ICIs efficacy in patients with NSCLC, and outlines their prognostic relevance in the era of immunotherapy.

Members of the DNA methyltransferase (DNMT) family have been recognized as major epigenetic regulators of altered gene expression during tumor development. They establish and maintain DNA methylation of the CpG island of promoter and non-CpG region of the genome. The abnormal methylation status of tumor suppressor genes (TSGs) has been associated with tumorigenesis, leading to genomic instability, improper gene silence, and immune evasion. DNMT1 helps preserve methylation patterns during DNA replication, whereas the DNMT3 family is responsible for de novo methylation, creating new methylation patterns. Altered DNA methylation significantly supports tumor growth by changing gene expression patterns. FDA-approved DNMT inhibitors reverse hypermethylation-induced gene repression and improve therapeutic outcomes for cancer. Recent studies indicate that combining DNMT inhibitors with chemotherapies and immunotherapies can have synergistic effects, especially in aggressive metastatic tumors. Improving the treatment schedules, increasing isoform specificity, reducing toxicity, and utilizing genome-wide analyses of CRISPR-based editing to create personalized epigenetic therapies tailored to individual patient needs are promising strategies for enhancing therapeutic outcomes. This review discusses the interaction between DNMT regulators and DNMT1, its binding partners, the connection between DNA methylation and tumors, how these processes contribute to tumor development, and DNMT inhibitors' advancements and pharmacological properties.

Chromobox 2 (CBX2), a crucial component of the polycomb repressive complex (PRC), has been implicated in the development of various human cancers. However, its role in the regulation of tumor immunogenicity and immune evasion remains inadequately understood. In this study, we found that ablation of CBX2 led to tumor growth inhibition, activation of the tumor immune microenvironment, and enhanced therapeutic efficacy of anti-PD1 or adoptive T cell therapies by using murine syngeneic tumor models. By analysis of the CBX2-regulated transcriptional program coupled with mass spectrometry screening of CBX2-interacting proteins, we found that CBX2 suppresses interferon signaling independent of its function in the canonical PRC. Mechanistically, CBX2 directly interacts with RACK1 and facilitates the recruitment of HDAC1, which attenuates the H3K27ac modification on the promoter regions of interferon-stimulated genes, thereby suppressing interferon signaling. Consequently, CBX2 reduces tumor immunogenicity and enables immune evasion. Moreover, a high expression level of CBX2 is associated with immune suppressive tumor microenvironment and reduced efficacy of immunotherapy across various human cancer types. Our study identifies a noncanonical CBX2-RACK1-HDAC1 corepressor complex in suppression of tumor immunogenicity, thereby presenting a potential target and biomarker for tumor immunotherapy.

Our previous study found that Achaete-scute complex homolog 1 (ASCL1) is involved in classifying BC subtypes with different prognostic and pathological characteristics. However, the biological role of ASCL1 in BC still remains largely unexplored. This study aims to elucidate the function of ASCL1 in BC using bioinformatics analyses, as well as in vitro and in vivo experimental approaches.

Data from the TCGA, GEO, and Human Protein Atlas databases were utilized to evaluate ASCL1 expression in BC and its association with patient prognosis. Genetic alterations in ASCL1 were assessed through the COSMIC and cBioPortal databases, while the TIMER2.0 database provided insights into the relationship between ASCL1 expression and key gene mutations in BC. The GDSC database was used to examine correlations between ASCL1 levels and sensitivity to standard chemotherapeutic agents. Associations between ASCL1 expression and cytokines, immunomodulatory factors, MHC molecules, and receptors were analyzed using Pearson and Spearman correlation methods. The TIP database was employed to investigate the connection between ASCL1 expression and immunoreactivity scores, and six computational approaches were applied to evaluate immune cell infiltration. Functional assays were conducted on BC cell lines MCF-7 and MDA-MB-231, and nude mouse models were used for in vivo studies.

ASCL1 was found to be upregulated in BC and correlated with unfavorable prognosis and mutations in key oncogenes. Its expression was linked to immunomodulatory factors, immune cell infiltration, and immunoreactivity scores in the tumor microenvironment. Additionally, ASCL1 influenced tumor immune dynamics and chemosensitivity in BC. Overexpression of ASCL1 enhanced BC cell proliferation, migration and invasion, while its knockdown had the opposite effect. Notably, inhibition of ASCL1 increased BC cell sensitivity to paclitaxel both in vitro and in vivo. In addition, inhibition of ASCL1 activated ferroptosis in BC, including altered mitochondrial morphology, increased MDA and ROS levels, decreased GSH levels and reduced GSH/GSSG ratio. Mechanistically, inhibition of ASCL1 decreases the phosphorylation of CREB1, thus reducing the expression of GPX4. In summary, inhibition of ASCL1 increases paclitaxel sensitivity by activating ferroptosis via the CREB1/GPX4 axis.

ASCL1 exerts oncogenic effects in BC and represents a potential therapeutic target for intervention.

Chemokines (chemotactic cytokines) play essential roles in developmental process, immune cell trafficking, inflammation, immunity, angiogenesis, cellular homeostasis, aging, neurodegeneration, and tumorigenesis. Chemokines also modulate response to immunotherapy, and consequently influence the therapeutic outcome. The mechanisms underlying these processes are accomplished by interaction of chemokines with their cognate cell surface G protein-coupled receptors (GPCRs) and subsequent cellular signaling pathways. Chemokines play crucial role in influencing aging process and age-related diseases across various tissues and organs, primarily through inflammatory responses (inflammaging), recruitment of macrophages, and orchestrated trafficking of other immune cells. Chemokines are categorized in four distinct groups based on the position and number of the N-terminal cysteine residues; namely, the CC, CXC, CX3C, and (X)C. They mediate inflammatory responses, and thereby considerably impact aging process across multiple organ-systems. Therefore, understanding the underlying mechanisms mediated by chemokines may be of crucial importance in delaying and/or modulating the aging process and preventing age-related diseases. In this review, we highlight recent progress accomplished towards understanding the role of chemokines and their cellular signaling pathways involved in aging and age-relaed diseases of various organs. Moreover, we explore potential therapeutic strategies involving anti-chemokines and chemokine receptor antagonists aimed at reducing aging and mitigating age-related diseases. One of the modern methods in this direction involves use of chemokine receptor antagonists and anti-chemokines, which suppress the pro-inflammatory response, thereby helping in resolution of inflammation. Considering the wide-spectrum of functional involvements of chemokines in aging and associated diseases, several clinical trials are being conducted to develop therapeutic approaches using anti-chemokine and chemokine receptor antagonists to improve life span and promote healthy aging.

Rapid advances in the field of epigenetics have facilitated the development of novel therapeutics targeting epigenetic mechanisms that are hijacked by cancer cells to support tumour growth and progression. Several epigenetic agents have been approved by the FDA for the treatment of cancer; however, the efficacy of these drugs is dependent on the underlying biology and drivers of the disease, with inherent differences between solid tumours and haematological malignancies. The efficacy of epigenetic drugs as single agents remains limited across most cancer types, which has spurred the clinical development of combination therapies, with the hope of attaining synergistic activity and/or overcoming treatment resistance. In this Review we discuss clinical advances that have been achieved with the use of epigenetic agents in combination with chemotherapies, immunotherapies or other targeted agents, including epigenetic-epigenetic combinations, as well as limitations and challenges associated with these combinatorial strategies. So far, the success of combination therapies targeting epigenetic mechanisms has generally been confined to haematological malignancies, with limited efficacy observed in patients with solid tumours. Nevertheless, this Review captures the field of epigenetic combination therapies across the spectra of haematology and oncology, highlighting opportunities for precision therapy to effectively harness the potential of epigenetic agents and produce meaningful improvements in clinical outcomes.

The EZH2 expression shows significantly associated with immunotherapeutic resistance in several tumors. A comprehensive analysis of the predictive values of EZH2 for immune checkpoint blockade (ICB) effectiveness in uveal melanoma (UM) remains unclear. We analyzed UM data from The Cancer Genome Atlas (TCGA) database, identified 888 differentially expressed genes (DEGs) associated with EZH2 expression, then conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses to elucidate biological features of EZH2 in UM assays. The correlation of the expression of EZH2 with tumor immunity related factors such as immune-related pathways, infiltration of various immune cells, immune score and immune checkpoints were explored. The evaluation of EZH2's capability to predict immune therapy outcomes in UM was assessed by incorporating the Tumor Immune Dysfunction and Exclusion (TIDE) score. Lastly, programmed death-ligand 1 (PD-L1) expression was detected in an independent UM patient cohort by immunohistochemical analyses, the correlation of EZH2 with PD-L1 was evaluated. Results highlighted that the EZH2 expression was correlated with immune-related pathways, infiltration of various immune cells, immune score, the expression of immune checkpoints and immunotherapy sensitivity. Collectively, we suggested that EZH2 might be considered as predictor on the therapeutic effects of ICBs on UM patients, and a potential target for combined immunotherapy.