The "picture" of the congenital genetic therapy. Nature's depth is good.

Text . . . At the heart of man-language oscientical genetics are various co-price modifications of histones and nucleic acids that co-regulate chromatin structure and gene expression.
disorders in the esotroviral genetic group drive abnormal transcription procedures and promote cancer occurrence and progression.
September 14th, in a recent review published in the journal Nature Reviews Drug Discovery entitled "Targeting the epigenetic regulation of antitumour immunity", four scientists from the University of Melbourne, Australia, summarized the effects of key abnormal epigenetic regulation - DNA methylation and histone translation modification - on tumor immunogeneticity, as well as epigenetic regulation against tumor immune cell function.
article emphasizes that small molecule inhibitors of exogenic genetic regulators are expected to be used to enhance anti-tumor immune response, and discusses the potential for anti-cancer combining exogenetic therapy with immunotherapy.
sources: Nature Reviews Drug Discovery I, the classification of oso-genetic drugs Each of the oso-genetic modifications is regulated by specific enzymes that can add or remove ostogenesic markers, known as "writers(W)" and "erasers(E)," respectively.
addition, specific protein domains that identify these modifications, known as "readers(R)," regulate the appearance of genetic modification.
disorders of the esophageal genetic group are prevalent in human cancer, which leads to the development of cancer-targeted predetermogeneous genetic therapy.
Figure 1 classifyes the fda-approved and on-the-look genetic therapies for targeted histoprotein acetylation, histoprotein methylation, DNA methylation, and histokine phosphatization regulatory factors by target.
Figure 1 - The treatment strategies for regulating the oscic genetic group (Source: Nature Reviews Drug Discovery) II, the mechanism by which the oscic genetic drug works DNA methylation regulator DNA methyl transferase (DNMT) of small molecule inhibitors (also known as hypomethylating agents, or demethylation agents) are the most widely used expedited genetic therapies in cancer treatment, mainly for the treatment of myeloid dysplomatic syndrome (MDS) and acute myeloid leukemia (AML).
the DNMT family catalyzed DNA from the head to methylation (responsible for DNMT3a and DNMT3b) and maintained DNA methylation after replication (by DNMT1).
the ten-eleven translocation (TET) family of α-ketone diacid dependence is thought to indirectly drive DNA demethylation through oxidation catalysis of 5-methyl cytosine (Figure 2a).
in human cancer, genes that regulate DNA methylation, including DNMT3A and TET2, often mutate, leading to abnormal PATTERNs of DNA methylation, which in turn is associated with gene expression disorders.
, for example, super-methylation of tumor suppressor genes and microRNAs is directly related to tumor occurrence (Figure 2b).
addition, studies have confirmed that DNA methylation disorders may be a major carcinogenic event, which may simultaneously alter the anti-tumor immune response and further exacerbate tumor occurrence.
direct anti-tumor effects (e.g. apoptosis, cell cycle blocking) triggered by DNMT inhibitors were initially attributed to the re-expression of genes that were silent due to DNA methylation.
later studies have shown that DNMT inhibitor therapy can also increase the expression of genes associated with antigen delivery and immunostulating molecules such as CD80, CD86, and CD40.
there is also evidence that DNMT inhibitors promote the delivery of new antigens in tumor cells and enhance immunogenicity.
Figure 2 - DNA methylation in cancer and viral morphological (Source: Nature Reviews Drug Discovery) DNA methylation is also widely used by eutroviruses to inhibit transcription of transposing factors, such as endogenous retroviruses that have been integrated into the host genome (endogenous retroviruses, ERVs, Figure 2c).
de-methylated drugs can re-express ERVs in tumor cells and stimulate congenital antiviral-like reactions (Figure 2d).
two-way transcription of ERVs produces a double-stranded RNA (dsRNA), which can then be sensed by pattern-recognized subjects including TLRs, cytosome subject MDA5, RIG-I, and cGAS-STING paths.
dsRNA perception pathway triggers a signal cascade involving MAVS aggregation, eventually evoking a congenative immune response by directly raising IFN alpha and IFN beta through inflammatory transcription factors such as IRF7, NF-B.
And self-secreted and side-secreted IFN alpha/β signals in the tumor microenvironment promote the production of inflammatory cytokines and tendination factors, thereby enhancing the immunogenicity of tumor cells (Figure 2e) and the efficacy of immunosuppression therapy.
, combining DNMT inhibitors with immunotherapy to trigger a more effective anti-tumor immune response and overcome adaptive resistance associated with immune checkpoints may be a viable strategy.
currently, a large number of clinical trials have been conducted to evaluate the union of DNMT inhibitors with checkpoint inhibitors (e.g. PD-1/PD-L1 antibodies, CTLA-4 antibodies) (Table 1).
Table 1 Clinical trial source: Nature Reviews Drug Discovery histoprotein acetylation regulator protein translation is highly dynamic and regulated by the opposite activity of histoprotein acetyl transferase (HATs) and histoprotein deacetylase (HDACs) (Figure 3a).
deacetylization, which is mediated by HDACs, is associated with chromatin concentration and transcriptional silence, often accompanied by an increase in histone methylation on the same residue.
Clinically, HDAC inhibitors have been widely studied over the past 20 years as an anti-cancer drug, and some drugs (Volinota, Romedisin, Pabis and Bellinsta) have been approved for the treatment of blood malignancies based on the efficacy of single-drug therapy.
, the therapeutic response of solid tumors to HDAC inhibitors depends on a combined treatment option.
in cancer models, HDAC inhibitors were less effective in immunosuppressive mice or after the depletion of immune cells in wild mice, indicating the presence of immune-dependent components in their mechanisms of action.
low affinity pan-HDAC inhibitors sodium valproate can induce the expression of NKG2D ligation MICA, ULBP2, and ULBP3 on tumor cells, leading to granulation enhancement of NK cells.
in mouse melanoma models, the Class I HDAC inhibitor Lormidsin enhanced MHC Class I molecular expression and increased cell dissolution activity in CD8-T cells.
HDAC inhibitors can also induce the expression of MHC Class I antigen processing and delivery genes (including TAP1, TAP2, LMP2, LMP7, and B2M) (Figure 3b;3c) and raise the immuno checkpoint libid (including PD-L1).
CLASS IV HDAC11-specific inhibitors were able to increase OX40L in Hodgkin's lymphoma, disrupting the immunosuppressive function of the regulatory T cells that produce IL-10.
, HDAC inhibitors regulate both positive and negative immune factors in tumor cells, thus regulating the identification of congenital and adaptive immune systems.
the immunomodulation activity of HDAC inhibitors provides a theoretical basis for their cooperation with immunotherapy.
in preclinical cancer models, multiple HDAC inhibitors enhance the efficacy of immuno-checkpoint blocking therapy, immunostature therapy, and step-by-step T-cell therapy.
the efficacy of these combination therapses is related to a variety of mechanisms, such as tumor-immersive lymphocytes, increased cytokine production, and increased T-cell activity.
based on these preclinical findings, clinical trials evaluating the combination of HDAC inhibitors with immunotherapy are under way (Table 1).
early clinical trial results showed significant clinical activity and acceptable safety in patients with melanoma who progressed after anti-PD-1 monotherapy or anti-PD-1 combined anti-CTLA-4 therapy.
Figure 3 - The role of hismoglobin acetylation and methylation in tumor occurrence and immunogenicity (Source: Nature Reviews Drug Discovery) Histoprotein methylation regulator histoglobin methylation pattern abnormalities are often detected in human cancer.
of histoprotein methyl transferases (HMTs) have been used as therapeutic targets, including EZH2, SETDB1, DOT1L, but only EZH2 and DOT1L small molecule inhibitors have entered clinical development.
EZH2 has been confirmed in a series of tumors.
addition, EZH2 is associated with immune escape mechanisms in a variety of tumor types, most notably by inhibiting antigen delivery mediated by MHC Class I molecules (Figure 3b, 3c).
other studies have confirmed that the supergenetic silencing of immunogenic factors mediated by histoprotein methylation is an important mechanism for cancer immune escape.
SETDB1 has been found to be ups and ups and ups in human cancer, suggesting its carcinogenic effects.
genetic loss of SETDB1 in AML cell line can effectively stimulate the production of viral anthropomorphism and type I interferon, thus inducing tumor cell death.
that although there are currently teams reporting small molecule inhibitors that can adequately selectively inhibit SETDB1, these inhibitors are expected to promote anti-tumor immunity.
DOT1L is histoprotein H3 lysine 79 (H3K79) methyl transferase.
the use of small molecular inhibitors to target DOT1L has been shown to be effective in preclinical and heterogeneian MLL (mixed-lineage leukaemia)-driven AML models, and these findings have pushed DOT1L inhibitor EPZ-5676 (pinometostat) into Phase I clinicalization.
whether the regulation of DOT1L-dependent immunomodulation genes plays any important role in tumor occurrence or anti-tumor immunity has yet to be determined.
3. In addition to exploring the mechanism of the role of the immune cells, the authors also summarize in detail how the metastatic genetic mechanism controls the fate and function of NK cells, CD4-plus and CD8-T lymphocytes in the anti-tumor immune response.
as shown in Figure 4a, EZH2 inhibitors enhance the expression of NKG2D on NK cells and NKG2DL on tumor cells.
this interaction leads to NK cell activation and tumor cell death.
, EZH2 inhibitors also increase the expression of NK cell negative regulatory factor MHC Class I molecules.
addition, the expression of NK cell-effect genes such as IFNG can be regulated by DNA methylation, so DNMT inhibitors are expected to be used to enhance the expression of these genes, thereby increasing cytotoxicity of NK cells.
figure 4. The metagenetic regulation of the anti-tumor activity of NK cells, CD4-T cells, and Treg cells (Source: Nature Reviews Drug Discovery) Figure 4b summarizes the metagenetic regulation of CD4-T cells.
inhibition of EZH2 can lead to increased differentiation of TH1 and TH2 cells.
addition, because SETDB1 limits the expression of TH1 cell-related genes, such as TBX21, inhibiting SETDB1 may enhance the response of TH1 cells and potentially promote anti-tumor immunity.
diagram 4c-e summarizes the oscic genetic regulation of regulatory T (Treg) cells.
HDAC9 and HDAC7 inhibitors promote FOXP3 activity and Treg cell function.
In addition, in immunosuppressive Treg cells, the use of EZH2 inhibitors or DNMT inhibitors can cancel the Treg cell-specific transcription procedure, resulting in the expression of Therag cell target genes (such as CTLA-4) and reduced overall immunosuppression.
, this use of EZH2 inhibitors, or DNMT inhibitors, increases the costration of antigen-presenting cells (APCs), resulting in an increased response of CD8-T cells.
figure 5. The overt genetic regulation of CD8-T cells (Source: Nature Reviews Drug Discovery) Figure 5 summarizes the oscic genetic regulation of CD8-T cells.
the central importance of CD8-T cells in anti-tumor immune response and virus removal, its metagenetic regulation has been widely studied.
Under the linear model of T cell differentiation, the initial T cells are gradually differentiated into stem cell memory T (TSCM) cells, followed by central memory T (TCM) cells, effect memory T cells, effect T (Teff) cells, and finally depleted T cells or end-of-life differentiated cells (Figure 5).
the activation of CD8-T cells can cause dynamic changes in DNA and histoprotein modification.
the cloning amplification of T cells from initial T cells to Teff cells is associated with different DNA methylation characteristics.
in tumor micro-environments, the expression of DNMT1 itself increased in CD8-T cells, which was associated with an increase in gene methylation associated with T-cell dysfunction, thereby inhibiting the anti-tumor esotypes of CD8-T cells.
, DNA methylation actively regulates the function of T-cell differentiation and effect T-cells, and limits the therapeutic response to immune checkpoint blocking.
is a potential treatment opportunity to maintain the status of respondable immuno-checkpoint blocking therapy through the ode to the genetic regulation of CD8-T cells.
preclinical studies have shown that combining PD-L1, PD-1, or CTLA-4 inhibitors with DNMT inhibitors led to more effective CD8-T cell anti-welling.