# Enhancement of EPR Effect for Passive Tumor Targeting: Current Status and Future Perspectives
## 2 Distinctive Characteristics of Tumor Microenvironment and Heterogeneity of EPR
### Components of Tumor Microenvironment
\begin{table}
\begin{tabular}{c c c} \hline \hline \multicolumn{3}{c}{**Components of the Tumor Microenvironment**} \\ \hline \multicolumn{3}{c}{**Cellular Components**} \\ \hline \multicolumn{3}{c}{_Component_} \\ \hline \multicolumn{3}{c}{_Characteristics_} \\ \hline \multirow{8}{*}{Immune cells} & 1. & _Tumor-associated immune cells:_ \\  & \(\bullet\) & CD8+ T cells (CTLs): Destroy cancer cells through apoptosis. \\  & \(\bullet\) & NK cells: Destroy cancer cells and enhance immunity. \\  & \(\bullet\) & Dendritic cells (DCs): Activate T cells through antigen presentation. \\  & \(\bullet\) & M1 macrophages: Produce pro-inflammatory cytokines against tumors. \\  & \(\bullet\) & N1 neutrophils: Kill cancer cells and induce an immune response. \\  & 2. & _Immune cells that promote tumor growth:_ \\  & \(\bullet\) & Tregs: Suppress immune response and reduce the effectiveness of CTLs. \\  & \(\bullet\) & MDSCs: Enhance angiogenesis and suppress T cells. \\  & 3. & _B cells: May either enhance the immune response or promote tumor growth._ \\ \hline \multirow{4}{*}{Adipocytes [31]} & \(\bullet\) & Secrete substances that support tumor growth. \\  & \(\bullet\) & Cancer cells activate lipolysis, releasing energy. \\  & \(\bullet\) & Leptin from adipocytes promotes tumor growth. \\  & \(\bullet\) & Adipocytes secrete MMPs that modify the extracellular matrix. \\ \hline \multirow{4}{*}{Mesenchymal stem cells (MSCs) [47]} & \(\bullet\) & Originate from bone marrow and other sites. \\  & \(\bullet\) & Differentiate into various types of cells. \\  & \(\bullet\) & Affect cancer cell behavior through the secretion of growth factors and cytokines and remodel the ECM. \\ \hline \multicolumn{3}{c}{**Non-cellular components**} \\ \hline \multicolumn{3}{c}{_Component_} \\ \hline \multicolumn{3}{c}{_Characteristics_} \\ \hline \multirow{4}{*}{Extracellular matrix (ECM) [31]} & \(\bullet\) & Structural support: Functions as a natural scaffold for cancer cells, providing a framework for their growth. \\  & \(\bullet\) & Metastasis: High levels of collagen and fibroblasts are associated with the development of dysplasia. \\  & \(\bullet\) & Remodeling: Proteases such as MMPs degrade the ECM, promoting tumor metastasis. \\  & \(\bullet\) & Storage and release of cytokines and growth factors (e.g., VEGF, FGF, PDGF, TGF-\(\beta\)) for angiogenesis and development. \\ \hline \multirow{4}{*}{Extracellular vesicles [48]} & \(\bullet\) & Facilitate communication between cancerous and stromal cells. \\  & \(\bullet\) & Promote inflammation, tumor progression, angiogenesis, and metastasis. \\  & \(\bullet\) & Hypoxia increases extracellular vesicle production and promotes the conversion of stromal cells to cancer-associated fibroblasts. \\ \hline \multirow{4}{*}{Chemokines [49]} & \(\bullet\) & Determine metastatic targets, influencing which organs metastatic tumors \\  & \(\bullet\) & preferentially target. \\  & \(\bullet\) & Support the interaction of cancer cells with the stromal environment. \\  & \(\bullet\) & Enhance migration and angiogenesis. \\  & \(\bullet\) & Influence of hypoxia: Increases the expression of chemokine receptors, thereby enhancing metastasis. \\  & \(\bullet\) & Affect the function and distribution of immune cells. \\ \hline \multirow{4}{*}{Growth factors [50]} & \(\bullet\) & Promote tumor cell growth and survival through binding to specific receptors. \\  & \(\bullet\) & Act locally rather than endocrinically, affecting nearby cellular interactions. \\ \cline{1-1}  & \(\bullet\) & Promote metastasis by regulating cell motility and survival. \\ \cline{1-1}  & \(\bullet\) & Influence interactions with the stromal environment, enhancing angiogenesis and tissue repair. \\ \cline{1-1}  & \(\bullet\) & Certain oncogenes are associated with growth factor receptors, affecting tumor development. \\ \hline \hline \end{tabular}
\end{table} 
Table 1: _Cont._The tumor microenvironment is influenced by factors such as the immune response and intracellular bacteria, such as _Fusobacterium nucleatum_.