CN-121971623-A - Application of FMR1 inhibitor in preparation of medicines for treating immune rejection type gastric cancer

Abstract

The invention discloses application of an FMR1 inhibitor in preparing a medicament for treating immune rejection type gastric cancer. Experimental studies prove that FTO is continuously and highly expressed in immune rejection phenotype and is related to interstitial activation and T cell rejection. Continuous immunohistochemistry and multiplex immunofluorescence showed that FMR1 protein was highly expressed in the immune-repulsive tumor microenvironment and CD8 + T cells were multipotent in the tumor stroma. Mechanically, FMR1 stabilizes FTO proteins and limits their proteasome degradation by post-translational regulation, thereby maintaining FTO-dependent m6A reprogramming, enhancing immune rejection microenvironment. Therefore, the invention discloses a non-classical mechanism of stabilizing the FTO protein by post-translational modification of the FMR1, and the FMR1-FTO axis can be used as a potential intervention target for breaking immune barrier and sensitizing gastric cancer immunotherapy.

Inventors

• WU FENGLEI
• MAO CHENXI
• HU NAN
• XU YIMENG
• ZHAO LUMING
• ZHOU KANGJIE
• HONG YIDONG
• ZHANG JINGZHOU

Assignees

• 连云港市第一人民医院

Dates

Publication Date

20260505

Application Date

20260303

Claims (8)

1. Application of FMR1 inhibitor in preparing medicine for treating immune rejection type gastric cancer.
2. 2. The use according to claim 1, wherein the FMR1 inhibitor is capable of enhancing the immunotherapeutic effect against gastric cancer by inhibiting FMR1 gene, reducing FTO protein expression, inhibiting gastric cancer immune rejection.
3. 3. The use according to claim 1, wherein the FMR1 inhibitor is a substance that inhibits FMR1 activity or expression.
4. 4. The use of claim 1, wherein the FMR1 inhibitor comprises a small molecule organic, a small molecule inorganic, an anti-FMR 1 antibody, a nucleic acid fragment or polypeptide capable of specifically binding to FMR1 and inhibiting its activity.
5. 5. The use of claim 1, wherein the FMR1 inhibitor comprises an inhibitor precursor.
6. 6. The use according to claim 1, wherein the FMR1 inhibitor is selected from the group consisting of artificially synthesized small interfering ribonucleic acids (siRNA) and short hairpin ribonucleic acids (shRNA).
7. 7. Use of a composition comprising an FMR1 inhibitor for the preparation of a medicament for the treatment of immune-repulsive gastric cancer.
8. 8. The use according to claim 7, wherein the composition comprises an FMR1 inhibitor and a pharmaceutically acceptable carrier or excipient.

Description

Application of FMR1 inhibitor in preparation of medicines for treating immune rejection type gastric cancer Technical Field The invention belongs to the technical field of immune rejection type gastric cancer treatment, and particularly relates to application of an FMR1 inhibitor in preparation of a medicament for treating immune rejection type gastric cancer. Background Gastric cancer (GASTRIC CANCER, GC) is a malignant tumor with the fifth incidence and mortality rate all around the world, and shows extremely high molecular and clinical heterogeneity. Although classical Lauren typing and the molecular subtype (e.g. EBV, MSI, GS, CIN) defined by the cancer genomic profile (TCGA) have largely constructed our cognitive framework for gastric cancer biology, the clinical transformation value of these traditional types has been significantly inadequate in guiding accurate oncology practices, particularly in predicting immunotherapeutic responses. Although immunotherapy, represented by Immune Checkpoint Blockade (ICB), remodels the therapeutic profile of advanced gastric cancer, clinical benefit remains limited, with Objective Remission Rate (ORR) of ICB of only 10% -26%, with the vast majority of patients facing primary resistance or treatment failure. To resolve this drug resistance bottleneck, the concept of tumor immunophenotype has been developed. Among them, the "Immune-repulsed" phenotype is particularly prevalent in gastric cancer. In this type of microenvironment, despite the abundance of immune cell infiltration, a dense matrix barrier (consisting essentially of cancer-related fibroblasts and their matrix deposits) physically blocks effector T cells spatially outside the tumor nest, forming a special "cold tumor" state. This unique spatial isolation severely limits anti-tumor immune killing and is a key mechanism leading to immunotherapeutic resistance. Although the abundance of immune infiltration is closely related to patient prognosis, the analysis of gastric cancer Tumor Immune Microenvironment (TIME) cell architecture and molecular driving force is still incomplete at present, and a robust typing system based on spatial features is not yet available to guide stratified treatment. N6-methyladenosine (m 6A) is the most common internal modification of eukaryotic mRNA, m6A playing a key role in tumor progression. Although the effect of m 6 a regulatory factors on tumor cell malignancy has been widely reported, it remains a blank how it induces a systemic mechanism of immune rejection phenotype by remodelling TIME. m6A demethylase FTO has been shown to be associated with immune escape of various tumors and is highly expressed in the gastric cancer immune rejection phenotype, but the upstream mechanism to maintain high stability of FTO protein in this phenotype is not yet clear. Disclosure of Invention Aiming at the problems in the prior art, the invention provides the application of the FMR1 inhibitor in preparing medicaments for treating immune rejection type gastric cancer. The invention firstly establishes a steady immune typing system based on space characteristics, and mainly analyzes molecular characteristics obviously related to an immune rejection phenotype. Further, we dissect deep into the core regulatory network of the FMR1-FTO axis from the post-transcriptional modification point of view. The research not only provides reasonable molecular explanation for abnormal accumulation of FTO in specific immunophenotype, but also provides a novel intervention target with potential clinical value for overcoming gastric cancer immunotherapy drug resistance by revealing the mechanism that FMR1 antagonizes ubiquitin-proteasome pathway to stabilize FTO protein. The technical scheme is that in order to achieve the aim of the invention, the invention adopts the following technical scheme: in a first aspect, the invention provides the use of an FMR1 inhibitor in the manufacture of a medicament for the treatment of immune-repulsive gastric cancer. As a specific embodiment, the FMR1 inhibitor can inhibit the FMR1 gene, reduce the expression of FTO protein, inhibit gastric cancer immune rejection reaction and improve the immune therapeutic effect of gastric cancer. As a specific embodiment, the FMR1 inhibitor is a substance that inhibits FMR1 activity or expression. As specific embodiments, the FMR1 inhibitor includes a small molecule organic, a small molecule inorganic, an anti-FMR 1 antibody, a nucleic acid fragment or polypeptide capable of specifically binding to FMR1 and inhibiting its activity. As a specific embodiment, the FMR1 inhibitor comprises an inhibitor precursor. As a specific embodiment, the FMR1 inhibitor is selected from the group consisting of artificially synthesized small interfering ribonucleic acid (siRNA) or short hairpin ribonucleic acid (shRNA). As a specific embodiment, the immune-repulsive gastric cancer is a tumor microenvironment with a unique spatial distribution architecture, al