A Methionine Allocation Nanoregulator for the Suppression of Cancer Stem Cells and Support to the Immune Cells by Epigenetic Regulation.
Time：2025/2/24 10:40:43 Views：177
Epigenetic dysregulation in tumors drives malignant progression, therapeutic resistance, and the formation of a pro-tumor immune microenvironment by altering gene expression and metabolic patterns. This uncontrolled metabolism fuels tumor proliferation and epigenetic plasticity, creating a vicious cycle. Recent studies reveal that tumors aggressively plunder nutrients, depriving immune cells of resources while sustaining their own growth. This process is facilitated by the upregulation of transporters and metabolic enzymes, driven by epigenetic and gene expression dysregulation. Targeting the critical link between tumor metabolism and epigenetics may offer therapeutic opportunities to disrupt this cycle, overcome chemoresistance, and reverse immune suppression. To this end, we developed a co-delivery nanoregulator (AS-F-NP) that targets tumor methionine uptake and combines with immunogenic chemotherapy. AS-F-NP, composed of oxaliplatin prodrug-crosslinked fluorinated polycations and siRNA targeting the methionine transporter Lat4, limits tumor methionine plundering and restores methionine levels in the microenvironment, enhancing immune cell function. In two lung metastasis models, AS-F-NP demonstrated significant potential in activating anti-tumor immunity and eliminating cancer stem cells. These findings were published in Advanced Science (IF=14.3) under the title "A Methionine Allocation Nanoregulator for the Suppression of Cancer Stem Cells and Support to the Immune Cells by Epigenetic Regulation."
Epigenetic dysregulation is a hallmark feature of nearly all human cancers, directly influencing tumor cell gene expression and phenotype, driving them into abnormal metabolic patterns to meet the material demands of dysregulated epigenetics. The dynamic equilibrium of epigenetic modifications relies on reversible modification properties, necessitating that tumor cells maintain an ample supply of metabolic precursors. This metabolic adaptability not only provides the basis for tumor resistance to therapeutic stimuli or transformation into drug-resistant phenotypes but also shapes a tumor microenvironment characterized by "nutrient deprivation" through nutrient competition, leading to impaired immune cell function. Studies have shown that histone/DNA methylation modifications are not only closely associated with the maintenance of cancer stem cell phenotypes, chemoresistance, and metastatic potential but also regulate the effector functions of immune cells such as CD8+ T cells, revealing the pivotal role of epigenetic and metabolic abnormalities in tumor malignant progression.
The active methyl groups required for histone/DNA methylation modifications are entirely dependent on exogenous methionine supply, leading to a unique methionine-addicted metabolic pattern in tumor cells. By significantly upregulating the expression of the transporter Lat4, tumor cells establish a competitive advantage in the microenvironment, on one hand, acquiring sufficient methyl donors to maintain epigenetic plasticity, and on the other hand, causing methionine depletion in the microenvironment, resulting in dysfunctional infiltrating immune cells. Based on patient-derived clinical samples and database analyses, we confirmed the specific high expression of Lat4 in tumor tissues, which is significantly correlated with the formation of an immunosuppressive microenvironment. Therefore, focusing on the methionine-addicted metabolism of tumor cells can both reverse epigenetic dysregulation-related drug resistance and reshape the immune microenvironment. However, due to the lack of small molecule inhibitors targeting Lat4, siRNA-based gene intervention has become a key strategy, though its efficacy highly depends on the circulatory stability and tumor-specific release capabilities of the delivery system.
In light of this, we developed a crosslinked fluorinated polycation/siRNA composite nanoregulator (AS-F-NP), which achieves efficient siRNA encapsulation and stable delivery through oxaliplatin (OXA)-crosslinked fluorinated low molecular weight polyethyleneimine. Its innovation lies in: (1) utilizing the high-reductive microenvironment within tumor cells to trigger precise drug release and carrier degradation, avoiding the in vivo accumulation toxicity of high molecular weight cationic polymers; (2) OXA not only serves as a direct tumor-killing chemotherapeutic agent but also activates antigen-presenting cells to initiate anti-tumor immune responses by inducing immunogenic cell death; (3) siLat4 simultaneously inhibits the excessive plundering of methionine by tumor cells, both blocking the evolution of cancer stem cell phenotypes to sensitize chemotherapy and restoring the effector functions of immune cells in the microenvironment to reverse immune suppression. Ultimately, in two lung metastasis tumor models, this nanoregulator significantly inhibited tumor progression, offering hope for therapeutic strategies targeting the malignant cycle of tumor metabolism and epigenetics.
Boyu Su, the PhD candidate from the School of Pharmacy, Fudan University, is the first author. Associate Professor Tao Sun and Professor Chen Jiang are the corresponding authors of this paper. The work was supported by grants from the National Natural Science Foundation of China, National Key R&D Program of China, Shanghai Municipal Science and Technology Major Project, and ZJLab.
For more information:https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202415207
