# 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  
Cancer constitutes a dynamic system of neoplastic cells interacting with a complex array of non-neoplastic cells and non-cellular components from local or distant host tissues, promoting the growth of complex tissues: tumors [30, 31, 32, 33, 34]. The tumor microenvironment (TME) consists of tumor cells, stromal tissue (immune cells, fibroblasts, myofib,lasts, cytokines, and vascular tissue), and the extracellular matrix (ECM) [35]. These elements form a complex and constantly evolving entity where tumor and noncancer cells maintain mutual interactions throughout tumor progression [32, 36, 37]. Basal lamina plays a critical role in these interactions, as it partially separates the parenchyma (the tumor core) from the stromal region (part of the TME). This separation is imperfect, with poorly defined boundaries, thus facilitating TME interactions that support survival, local invasion, metastatic spread, and tumor cell response to therapeutic drugs, as well as angiogenesis and extracellular signaling [31, 32, 36, 37]. Cancer cells arise from genetic and epigenetic alterations, acquiring characteristics such as autonomous proliferation, resistance to cell death, invasion, immune evasion, reproductive immortality, and the ability to metastasize [38]. They invade healthy tissues and spread to different parts of the body through the lymphatic and circulatory systems [36, 39]. In addition, tumors can eliminate diverse cancer cells and microenvironments, contributing to their heterogeneity [31, 36]. A typical example is cancer stem cells that contribute to self-renewal (leading to carcinogenesis) and immune tolerance [36]. Tumor heterogeneity is intensified as the cancer progresses, in parallel with the maturation of cellular and non-cellular components of the TME [40]. The TME varies according to the type of cancer, showing heterogeneity; however, the consistent features include non-malignant cells and extracellular components of the host feeding on a vascular network [36, 41]. These components stimulate uncontrolled cell proliferation and play a vital role in all stages of carcinogenesis and tumor progression, such as in blood vessel development, by supporting tumor metabolism [30, 36]. Furthermore, the primary function of stromal factors is to structure and remodel functional ones [42]. Specifically, the key stromal cells of the TME include fibroblasts, cancer-associated fibroblasts (CAFs), pericytes, vascular cells (endothelial and wall cells), and immune cells, including T and B lymphocytes, natural killer cells, and tumor-associated macrophages [33, 40, 43]. Additional cell types include mesenchymal stem cells, peripheral adipocytes, and neurons [43]. Some investigators consider specialized cell types, such as endothelial cells, pericytes, adipocytes, and immune cells, to be non-stromal but still contribute significantly to tumor growth, metastasis, and therapeutic resistance [42]. Another categorization of noncancerous cells and components of the TME includes immune cells, blood cells, endothelial cells, adipocytes, and the stroma, which consists of specialized connective tissue cells such as fibroblasts, mesenchymal stromal cells, osteoblasts, and chondrocytes, as well as the extracellular matrix (ECM), which supports functional tissues [42]. Non-cellular chemical-physical elements such as the extracellular matrix (ECM) and soluble factors such as chemokines, cytokines, growth factors, extracellular vesicles, signaling molecules, and antibodies also play a critical role [32; 38; 40; 44]. Interventional studies involving animals or humans and other studies requiring ethical approval should indicate the authority that granted the approval and the corresponding ethical approval code. Table 1 summarizes the primary components of TME and their respective roles.