What is the tumor microenvironment?

 

The tumor microenvironment (TME) serves as the “soil” in which tumors grow, comprising tumor cells, immune cells, fibroblasts, vascular endothelial cells, and other components. It not only influences tumor invasion and metastasis but also determines whether the immune system can “recognize” and attack cancer cells. However, traditional monochromatic staining under the microscope has been insufficient to capture the complexity of the TME. It was not until the advent of multiplex immunohistochemistry (mIHC) that scientists were able to comprehensively profile the key players within the TME.

 

1、Tumor Cells

 

• Marker: Pan-CK (Cytokeratin), used to identify tumor cells themselves, is a commonly used epithelial cell marker.

• Function: As the core of the tumor microenvironment, tumor cells regulate the behavior of surrounding cells through the secretion of factors (such as growth factors and chemokines).

 

2、Stromal Cells

 

• Vascular Endothelial Cells: Markers include CD31 and VE-cadherin (endothelial cell markers). Endothelial cells form vascular networks to supply tumors with oxygen and nutrients, participating in tumor angiogenesis.

• Cancer-Associated Fibroblasts (CAFs): Markers include α-SMA (α-smooth muscle actin) and FAP (fibroblast activation protein). CAFs provide a supportive microenvironment for tumor cells by secreting extracellular matrix (ECM) components (such as collagen and fibronectin) and various growth factors (such as TGF-β and HGF), and they promote angiogenesis and immune suppression.

3、Immune Cells

 

• Macrophages（TAMs）

M1-type (Antitumor): CD86+/CD163−, secreting TNF-α, iNOS, etc.

M2-type (Pro-tumor): CD86−/CD163+, secreting Arginase, IL-10, etc.

 

 

• Neutrophils:CD16+, CD66b+, involved in inflammatory responses and tumor infiltration.

• Dendritic Cells: CD11c+, HLA-DR+, mediating antigen presentation and immune activation.

 

• T Cells

Cytotoxic T Cells (CD8+): CD8+, Granzyme+, Perforin+, directly killing tumor cells.

Regulatory T Cells (Tregs): CD3+, CD4+, Foxp3+, suppressing antitumor immunity.

 

• B Cells: CD20/CD19, Plasma Cells CD138+, involved in humoral immunity.

• Natural Killer Cells (NK): CD56+, killing tumor cells through the ADCC (Antibody-Dependent Cellular Cytotoxicity) mechanism.

4、Immune Checkpoint Molecules

 

• PD-1/PD-L1: Used to assess the state of immune suppression, often co-stained with CD8+ T cells.

• TIM-3, LAG3: Associated with T cell exhaustion, used to distinguish between “hot” and “cold” tumor microenvironments.


5、Spatial Distribution and Interactions

 

• Localization of Immune Cell Subsets: Distinguishing intratumoral and peritumoral regions using markers such as CD8+, CD3+, and CD45.

• Cell-Cell Crosstalk: Analyzing the co-localization and functional associations of macrophages, T cells, CAFs, and other cell types.


Technical Advantages 

 

Multicolor immunohistochemistry (mIHC) technology, utilizing multiplex fluorescent staining (such as TSA amplification technology), enables qualitative, quantitative, and spatial analysis, allowing for the simultaneous detection of multiple markers to reveal the spatial relationships and functional states between cells. For instance, in pancreatic cancer research, mIHC can simultaneously detect CD68 (macrophages), CD163 (M2 marker), PanCK (tumor cells), etc., while in lung cancer, it focuses on CD8+ T cells, PD-L1, Tregs, and others.

 

Application Scenarios

 

• Tumor Prognostic Assessment: Predicting patient survival rates through the analysis of immune cell density and subsets (such as T cell infiltration, Treg proportion).

• Validation of Immune Therapy Targets: Evaluating the correlation between PD-1/PD-L1 expression and the efficacy of immune checkpoint inhibitors.

• Study of Tumor Heterogeneity: Elucidating differences in cellular composition across various tumor regions (such as hypoxic areas, necrotic areas).

Future Perspectives: From the “Battlefield” to the “Battlefield Commander”

 

With the continuous optimization of mIHC technology, scientists are attempting to integrate it with spatial transcriptomics, single-cell sequencing, and other techniques to construct more refined maps of the tumor microenvironment (TME). In the future, it may be possible to develop personalized immunotherapy plans for each patient through “customized” analyses—truly empowering the immune system to become the “ace” in the fight against cancer.

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