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Tumor Microenvironment: Crosstalk Between Epigenetics, Metabolism and Immunity
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Tumor Microenvironment: Crosstalk Between Epigenetics, Metabolism and Immunity

A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 31 January 2026 | Viewed by 3175

Special Issue Editor

Dr. Liang Chen

E-Mail Website
Guest Editor
School of Medicine, Chongqing University, Chongqing, China
Interests: exosomes; metastatic spinal tumors; spinal trauma; intervertebral disc disease; degenerative spinal diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tumors are known to be highly heterogeneous, with a proclivity for aggressive metastasis and drug resistance. These characteristics are linked to the tumor microenvironment, wherein tumor cells undergo metabolic reprogramming and epigenetic modifications; immune cells also produce reprogramming modifications. Because of these modifications, the tumor microenvironment becomes immunosuppressive, rendering tumor cells more susceptible to immune escape and drug resistance. This Special Issue aims to explore the interplay between epigenetic modifications, metabolic reprogramming, and immune escape mechanisms in the tumor microenvironment. By targeting these processes, the mechanisms of tumor therapeutic resistance can be better understood, thus providing potential targets and solutions for novel therapies, such as clinical immunotherapy.

We thank Dr. Xinyue Wan from Chongqing University for his contributions to this Special Issue’s proposal, development and promotion.

Dr. Liang Chen
Guest Editor

Manuscript Submission Information

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Keywords

  • tumor microenvironment
  • epigenetic modifications
  • metabolic reprogramming
  • immune escape
  • tumor metastasis
  • therapeutic resistance

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Published Papers (4 papers)

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Research

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28 pages, 2347 KB  
Article
Interpretable Transfer Learning for Cancer Drug Resistance: Candidate Target Identification
by Wenjie Zhang, Xisong Wu, Liang Chen and Xinyue Wan
Curr. Issues Mol. Biol. 2025, 47(9), 753; https://doi.org/10.3390/cimb47090753 - 12 Sep 2025
Viewed by 346
Abstract
Tumor drug resistance exhibits substantial heterogeneity across cancer types, reflecting distinct molecular mechanisms in each malignancy. To characterize this complexity, we developed a pan-cancer transfer learning framework that integrates bulk RNA-seq data with a residual variational autoencoder (Res VAE) backbone. Five models were [...] Read more.
Tumor drug resistance exhibits substantial heterogeneity across cancer types, reflecting distinct molecular mechanisms in each malignancy. To characterize this complexity, we developed a pan-cancer transfer learning framework that integrates bulk RNA-seq data with a residual variational autoencoder (Res VAE) backbone. Five models were trained on the Genomics of Drug Sensitivity in Cancer (GDSC) dataset, which includes drug response profiles for 72 chemotherapeutic agents. Among them, three models are specially designed by incorporating variational autoencoders and large pretrained models (LLMs): the LLM large VAE (VAE_LL), the LLM small VAE (VAE_LS), and the LLM distillation VAE (VAE_LD). Random Forest (RF) and eXtreme Gradient Boosting (XGB) were included as ensemble learning baselines. After internal cross-validation, the top four models (VAE_LL, VAE_LD, XGB, and RF) were applied to five representative TCGA cohorts comprising 1,836 patients. For each cancer type, resistance to nine clinically relevant first-line drugs was modeled, resulting in 180 drug–cancer prediction tasks. Among all models, VAE_LD achieved the best overall performance, with a mean AUC of 0.81 and an F1 score of 0.92 on the GDSC benchmark, and maintained strong predictive power in the clinical validation phase. Interpretation analyses identified tumor-specific resistance biomarkers with clinical significance. In lung adenocarcinoma, elevated expression of TFF1 was repeatedly associated with resistance to Gefitinib and correlated with poor patient prognosis, indicating its potential as a therapeutic target. In glioblastoma, OPALIN, LTF, IL2RA, and SLC17A7 were implicated in Temozolomide resistance through pathways related to epithelial differentiation and angiogenesis. In conclusion, the VAE_LD model offers a high-performing and interpretable approach for predicting drug resistance across multiple tumor types. It supports the identification of clinically actionable biomarkers and provides a robust framework for precision oncology applications. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Crosstalk Between Epigenetics, Metabolism and Immunity)
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19 pages, 3108 KB  
Article
Caprylic Acid Restores Branched-Chain Amino Acid Metabolism in a Mouse Cachexia Model
by Isao Kawahara, Rina Fujiwara-Tani, Takuya Mori, Shota Nukaga, Ryoichi Nishida, Yoshihiro Miyagawa, Kei Goto, Hitoshi Ohmori, Kiyomu Fujii, Yi Luo, Takamitsu Sasaki, Chie Nakashima, Ruiko Ogata and Hiroki Kuniyasu
Curr. Issues Mol. Biol. 2025, 47(5), 325; https://doi.org/10.3390/cimb47050325 - 1 May 2025
Viewed by 937
Abstract
Cancer-associated sarcopenia is closely linked to the prognosis of cancer patients, making its management a critical aspect of cancer treatment. Branched-chain amino acids (BCAAs) are known to promote skeletal muscle growth in healthy individuals; however, their efficacy in cancer patients remains controversial. In [...] Read more.
Cancer-associated sarcopenia is closely linked to the prognosis of cancer patients, making its management a critical aspect of cancer treatment. Branched-chain amino acids (BCAAs) are known to promote skeletal muscle growth in healthy individuals; however, their efficacy in cancer patients remains controversial. In this study, we investigated the effects of BCAAs on cancer-associated sarcopenia to identify the underlying mechanisms that may suppress their effectiveness. In both a mouse cachexia model and an in vitro cachexia model, BCAAs did not significantly reduce oxidative stress, improve oxidative phosphorylation, suppress cytokine production, or enhance muscle mass and maturation, as observed in non-cancer-bearing models. Furthermore, treatment with 5-fluorouracil exacerbated sarcopenia in the mouse cachexia model, independent of tumor weight reduction, and this deterioration was not ameliorated by a BCAA-supplemented diet. The ineffectiveness of BCAAs was attributed to impaired BCAA catabolism, characterized by the decreased expression of branched-chain α-ketoacid dehydrogenase (BCKD) and increased levels of its inactive phosphorylated form, which were driven by elevated expression of BCKD kinase. These metabolic alterations were induced by high-mobility group box-1 (HMGB1). Notably, caprylic acid reversed these impairments in BCAA metabolism, thereby restoring BCAA efficacy. Our findings suggest that enhancing BCAA metabolism may improve their therapeutic potential in the treatment of cancer-associated sarcopenia. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Crosstalk Between Epigenetics, Metabolism and Immunity)
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Review

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36 pages, 1461 KB  
Review
Crosstalk Between Metabolic Reprogramming and Epigenetic Modifications in Colorectal Cancer: Mechanisms and Clinical Applications
by Yu-Hui Sun, Jing-Xian Zhang, Han-Shu Jin and Jin Huang
Curr. Issues Mol. Biol. 2025, 47(9), 751; https://doi.org/10.3390/cimb47090751 - 12 Sep 2025
Viewed by 466
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract in developing countries. It exhibits significant metabolic reprogramming and epigenetic abnormalities during its development. These two changes interact at the molecular level and jointly promote the progression of [...] Read more.
Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract in developing countries. It exhibits significant metabolic reprogramming and epigenetic abnormalities during its development. These two changes interact at the molecular level and jointly promote the progression of tumor cells. Cancer cells reprogram metabolites such as glucose, glutamine, and lipids to meet their energy and biological substrate requirements for survival. Concurrently, abnormalities in epigenetic modifications drive imbalances in gene expression and sustain the malignant phenotype. More importantly, metabolites can serve as substrates or cofactors for epigenetic enzymes, and changes in metabolic status can induce epigenetic remodeling. Correspondingly, epigenetic mechanisms regulate the transcription and function of metabolism-related genes, leading to adaptive alterations in tumor metabolic pathways. This review systematically summarizes the characteristics of major metabolic pathway reprogramming and the mechanisms underlying key epigenetic abnormalities in CRC. Furthermore, it elaborates on the mechanisms of their mutual influence in signaling pathways, key factors, immunometabolism, and the tumor microenvironment. It also discusses recent advances in novel diagnostic technologies (such as multi-omics integrated diagnostics) and therapeutic strategies (including targeting metabolism, epigenetic therapy, and combination therapies). In the future, research focusing on the interaction between metabolic reprogramming and epigenetics will provide new insights and targets for the early diagnosis and precision treatment of CRC. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Crosstalk Between Epigenetics, Metabolism and Immunity)
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18 pages, 435 KB  
Review
Molecular and Glycosylation Pathways in Osteosarcoma: Tumor Microenvironment and Emerging Strategies Toward Personalized Oncology
by Georgian Longin Iacobescu, Antonio-Daniel Corlatescu, Horia Petre Costin, Razvan Spiridonica, Mihnea-Ioan-Gabriel Popa and Catalin Cirstoiu
Curr. Issues Mol. Biol. 2025, 47(8), 629; https://doi.org/10.3390/cimb47080629 - 7 Aug 2025
Viewed by 840
Abstract
Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, which is also considered an aggressive disease due to its rapid growth rate, ability to metastasize early, and complex and heterogeneous tumor microenvironment (TME). Although we are developing improved surgical [...] Read more.
Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, which is also considered an aggressive disease due to its rapid growth rate, ability to metastasize early, and complex and heterogeneous tumor microenvironment (TME). Although we are developing improved surgical and chemotherapeutic approaches, the presence of metastatic or recurrent disease is still detrimental to the patient’s outcome. Major advances in understanding the molecular mechanisms of OS are needed to substantially improve outcomes for patients being treated for OS. This review integrates new data on the molecular biology, pathophysiology, and immune landscape of OS, as well as introducing salient areas of tumorigenesis underpinning these findings, such as chromothripsis; kataegis; cancer stem cell dynamics; and updated genetic, epigenetic, and glycosylation modifiers. In addition, we review promising biomarkers, diagnostic platforms, and treatments, including immunotherapy, targeted small molecule inhibitors, and nanomedicine. Using genomic techniques, we have defined OS for its significant genomic instability due to TP53 and RB1 mutations, chromosomal rearrangements, and aberrant glycosylation. The TME is also characterized as immunosuppressive and populated by tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, ultimately inhibiting immune checkpoint inhibitors. Emerging fields such as glycomics and epigenetics, as well as stem cell biology, have defined promising biomarkers and targets. Preclinical studies have identified that glycan-directed CAR therapies could be possible, as well as metabolic inhibitors and 3D tumor models, which presented some preclinical success and could allow for tumoral specificity and enhanced efficacy. OS is a biologically and clinically complex disease; however, advances in exploring the molecular and immunologic landscape of OS present new opportunities in biomarkers and the development of new treatment options with adjunctive care. Successful treatments in the future will require personalized, multi-targeted approaches to account for tumor heterogeneity and immune evasion. This will help us turn the corner in providing improved outcomes for patients with this resilient malignancy. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Crosstalk Between Epigenetics, Metabolism and Immunity)
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