tumor microenvironment

Overview

The tumor microenvironment (TME) refers to the complex, dynamic ecosystem surrounding and infiltrating a malignant tumor, comprising not only cancer cells but also a heterogeneous mixture of stromal cells, immune cells, extracellular matrix components, blood vessels, and soluble signaling molecules. Far from being a passive bystander, the TME actively participates in regulating tumor initiation, progression, immune evasion, metastasis, and therapeutic resistance. Key cellular constituents include tumor-associated macrophages (TAMs), cytotoxic T cells, regulatory T cells, dendritic cells, natural killer (NK) cells, B cells, cancer-associated fibroblasts, myeloid-derived suppressor cells (MDSCs), and neutrophils, all of which engage in intricate bidirectional crosstalk with neoplastic cells through cytokines, chemokines, Metabolites, and exosomes. The physical and chemical characteristics of the TME — including hypoxia, acidosis, elevated reactive oxygen species (ROS), and immunosuppressive metabolite gradients — collectively shape a milieu that frequently supports tumor survival and shields cancer cells from immune surveillance.

A defining hallmark of many TMEs is their immunosuppressive character, which drives resistance to both conventional therapies and modern immunotherapy. This immunosuppression is orchestrated through multiple overlapping mechanisms: the polarization of macrophages toward an M2-like, pro-tumorigenic phenotype; the accumulation of regulatory T cells and MDSCs; the co-expression of immune checkpoint molecules such as PD-1, PD-L1, LAG-3, TIGIT, VISTA, and B7-H3 (CD276); and the secretion of immunosuppressive cytokines such as transforming growth factor-beta (TGF-β) and IL-10. Understanding and therapeutically reprogramming the TME has emerged as one of the central challenges and opportunities in contemporary oncology, driving research across virtually every cancer type and treatment modality.

Recent Publications Focus

Below is a summary of the newest research publications targeting tumor microenvironment (sorted by publication date).

Recent studies have continued to position the tumor microenvironment as a central determinant of therapy response, immune escape, and disease progression across multiple cancers. In Kras-mutant lung adenocarcinoma, integrative bulk and single-cell analyses linked galactose metabolic reprogramming in epithelial cells to reduced immune infiltration and immunotherapy resistance, and identified KDM5A as a key predictor of immune checkpoint blockade resistance. In this setting, targeting KDM5A with the inhibitor CPI-455 sensitized Kras-mutant LUAD cells to immunotherapy in animal experiments and flow cytometry validation. A separate LUAD study focused on 3D chromatin architecture-related genes to examine postoperative recurrence, sorafenib response, tumor progression, and regulation of the tumor microenvironment, using integrative machine learning and spatial single-cell mapping.

Other recent work has used multi-omics and single-cell approaches to define tumor microenvironment-associated signatures in additional malignancies. In osteosarcoma, ecDNA-related genes were investigated for their association with prognosis and the tumor microenvironment using integrated single-cell and bulk transcriptomic analyses. In neuroendocrine prostate cancer, an integrated bulk and single-cell transcriptomic study was designed to define a ubiquitination-centered signature and tumor microenvironment circuits relevant to diagnosis and therapy. In triple-negative breast cancer, proteomic studies highlighted protein biomarkers involved in immune checkpoints, cell-surface glycoproteins, and regulators of tumor microenvironment interactions, with potential utility for predicting chemotherapy response and disease progression.

Several reviews and platform-focused studies emphasized therapeutic strategies that modulate the tumor microenvironment to improve cancer immunotherapy. In cervical cancer, emerging approaches discussed included tumor microenvironment modulation alongside checkpoint inhibitors such as pembrolizumab and cemiplimab, therapeutic cancer vaccines, and adoptive cell therapies, with the goal of overcoming resistance in immunologically “cold” tumors and recurrent/metastatic disease. A review of metal-organic framework-based drug delivery systems described how MOFs can be engineered to influence the tumor microenvironment and support combination immunotherapy with chemotherapy, radiotherapy, photodynamic therapy, sonodynamic therapy, chemodynamic therapy, photothermal therapy, and microwave therapy. Another review on lung cancer organoids highlighted advances in constructing the tumor microenvironment in organoid models to better mimic in vivo lung cancer biology and support immunotherapy research.

Across these publications, the tumor microenvironment is consistently presented as both a biomarker-rich ecosystem and a therapeutic target. Marine-derived anticancer compounds were also reviewed as agents that can influence the tumor microenvironment in addition to suppressing proliferation and inducing programmed cell death. Together, these studies underscore a growing emphasis on integrating transcriptomics, single-cell profiling, proteomics, spatial mapping, and engineered delivery or model systems to understand and manipulate the tumor microenvironment for improved cancer treatment.

Background PMIDs

• [PMID 41186264]
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Method PMIDs

• [PMID 41713140]
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Result PMIDs

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Target PMIDs

• [PMID 41512917]
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Conclusion PMIDs

• [PMID 41496304]
• [PMID 41662930]
• [PMID 41936028]
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