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CN-122005800-A - Application of CH25H in treating intestinal cancer

CN122005800ACN 122005800 ACN122005800 ACN 122005800ACN-122005800-A

Abstract

The invention discloses an application of CH25H in treating intestinal cancer, and belongs to the field of disease treatment. The present invention focuses on the cholesterol metabolite 25-hydroxycholesterol (25 HC) and aims at systematically elucidating its key mechanism of action in macrophage metabolic reprogramming, TME remodeling and immunotherapy sensitization. The research not only fastens the international tumor immune metabolism front, but also provides a definite transformation direction for breaking through the bottleneck of colorectal cancer immunotherapy.

Inventors

  • WEI WENXIA
  • LI MENGHONG

Assignees

  • 中山大学附属第六医院

Dates

Publication Date
20260512
Application Date
20260129

Claims (10)

  1. 1. The use of CH25H in macrophages in the manufacture of a medicament for the treatment of colorectal cancer, characterized in that CH25H is the target of action of the medicament.
  2. 2. The use of claim 1, wherein the medicament promotes CH25H expression in macrophages.
  3. 3.25HC in the preparation of medicine for treating intestinal cancer.
  4. 4. The use according to claim 1, wherein the bowel cancer is colorectal cancer.
  5. 5.25 HC combined PD-1 resisting medicine for treating intestinal cancer.
  6. 6. The use according to claim 5, wherein the bowel cancer is colorectal cancer.
  7. 7. A medicament for treating intestinal cancer, which is characterized by comprising 25HC.
  8. 8. A medicament for treating intestinal cancer, which is characterized by further comprising 25HC and PD-1.
  9. 9. The medicament according to claim 7 or 8, wherein the intestinal cancer is colorectal cancer; The drug does not contain a mitochondrial OXPHOS inhibitor and/or a fatty acid oxidation specific inhibitor.
  10. 10. The medicament of claim 9, wherein the mitochondrial OXPHOS inhibitor comprises either or both of rotenone and oligomycin; The fatty acid oxidation specific inhibitor is etodolac.

Description

Application of CH25H in treating intestinal cancer Technical Field The invention relates to the field of disease treatment, in particular to an application of CH25H in treating intestinal cancer. Background Colorectal cancer (Colorectal Cancer, CRC) is a malignant tumor that severely threatens human health worldwide, and its increased incidence is closely related to metabolic disorders such as high-fat diet, obesity, etc. Although immune checkpoint Inhibitors (ICBs) have revolutionized tumor therapy, they have little efficacy in the vast majority of microsatellite stabilized (MSS) colorectal cancer patients, suggesting that immunosuppressive Tumor Microenvironment (TME) is a core bottleneck limiting ICB efficacy, and there is a strong need to find key nodes for intervention from the metabolic level. Lipid metabolism reprogramming is a well-recognized hallmark of tumors. Obesity and hyperlipidemia are both risk factors for colorectal cancer, and previous studies have focused on cancer cells themselves, whereas tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations in tumor microenvironments, which play a key role in suppressing host anti-tumor immune responses and promoting tumor progression by shaping the immunosuppressive microenvironment. Then, it would be of great importance to investigate whether the oncological properties of TAMs can be reversed by actively intervening in their metabolic state, thereby eliciting anti-tumor immunity. Targeting the metabolic pathways of TAMs, performing "metabolic reprogramming" to convert them from "surprise" to "alliance" to kill the tumor would be a very potential new strategy for tumor immunotherapy. Disclosure of Invention The present invention focuses on cholesterol metabolite 25-hydroxycholesterol (25 HC) and aims at systematically elucidating its key mechanism of action in macrophage metabolic reprogramming, immunosuppressive Tumor Microenvironment (TME) remodeling and immunotherapy sensitization. The research of the invention not only tightens the international tumor immune metabolism front, but also provides a definite transformation direction for breaking through the bottleneck of colorectal cancer immune treatment. The invention discovers key molecules, namely, early-stage researches show that the expression of cholesterol metabolism key enzyme CH25H and metabolic product 25HC thereof in macrophages is significantly reduced in a colorectal cancer model induced by High Fat Diet (HFD) and a high cholesterol patient. This is the origin of linking the abnormal cholesterol metabolism with immunosuppression. Functional verification by constructing a mouse model of macrophage specific knockout of CH25H, confirming that CH25H deletion drives macrophages to polarization toward a tumor-promoting phenotype (M2-like) and inhibits the function of CD8 + T cells, thereby promoting tumor progression. Mechanism analysis-target spot discovery the key rate limiting enzyme CPT1A of Fatty Acid Oxidation (FAO) is a direct acting target spot of 25HC in macrophages. Mechanism analysis-molecular switch model an innovative model is presented that 25HC releases the inhibition of the endogenous inhibitor malonyl-CoA (MCoA) by competitive binding to CPT1A, thus "unlocking" the enzymatic activity of CPT 1A. Mechanism resolution-metabolic signaling activated CPT1A drives the FAO-oxidative phosphorylation (OXPHOS) metabolic axis, producing large amounts of acetyl-CoA (AcCoA). AcCoA is used as acetyl donor to activate NF- κB and other pro-inflammatory signal channels through acetylation modification (such as acetylation transcription factor p65 and histone H3K 27). Functional output and therapeutic prospects the molecular events ultimately drive macrophage reprogramming to an anti-tumor phenotype (M1-like) and enhance the killing function of CD8 + T cells. In an animal model, exogenous supplementation of 25HC can not only inhibit tumor by a single drug, but also generate a synergistic effect with an anti-PD-1 antibody, thereby providing a brand-new sensitization strategy for the immunotherapy of colorectal cancer. Drawings Figure 1. High fat diet drives immunosuppressive TME and bowel cancer progression by down-regulating macrophage CH 25H. a, a schematic diagram of MC38 subcutaneous transplantation tumor model experimental design (left), a MC38 tumor growth curve (right), b, weighing MC38 tumors (left), photographing tumors (right), c, detecting the expression levels of CD86, CD206 and Arg1 in MC38 tumor TAMs by flow cytometry, d, detecting the expression levels of effector molecules GzmB, TNF-alpha and IFN-gamma of MC38 tumor CD8 + T cells by flow cytometry, e, a schematic diagram of a separation flow of tumor TAMs of a standard diet and high-fat diet mouse (left), a schematic diagram of an extraction flow of peripheral blood hMDMs of a high-low cholesterol intestinal cancer patient (right), and collecting a cell delivery transcriptome for sequencing. f, n