Table 1 Major components (stromal cells, immune cells, ECM and secreted molecules) of the tumor microenvironment

Stromal cells

CAFs

CAFs are a highly heterogeneous cell population in both origin and functionality. Even though the majority of CAFs result from the induction and expansion of local tissue-resident fibroblasts, various studies have shown that CAFs originate from pericytes, adipocytes, endothelial cells, and bone marrow-derived mesenchymal stem cells. CAFs, which are the most abundant stromal cells in the TME, can promote tumorigenic by secreting cytokines and initiate the remodelling of the ECM. CAFs can also stimulate angiogenesis, tumor formation and metastasis. Hence CAFs themselves and downstream effectors are potential targets for improving the sensitivity of antitumor therapies. Expression pattern of some CAFs surface markers include α-SMA, SPARC, and PDGFβ

43–45

MSCs

MSCs are a subset of heterogeneous non-hematopoietic fibroblast-like multipotent progenitor cells with immuno-suppressive properties. MSCs possess a high capacity for self-renewal while maintaining their multipotency. MSCs can differentiate into several types of cells, such as osteoblasts, chondrocytes, myocytes, and adipocytes. MSCs are found in nearly all tissues but are mostly located in perivascular niches, playing a remarkable role in tissue repair and regeneration. MSCs are found within most tumors and influence the formation and function of the TME. MSCs support cancer growth by differentiating into other pro-tumorigenic stromal components, enhancing the EMT, augmenting cancer cell survival, promotion cancer metastasis, endorsing angiogenesis, and suppressing the immune response

46–47

Pericytes

Pericytes are mural cells located between the endothelial cells of capillaries and the basement membrane, playing a crucial role in maintaining vascular function and blood flow. Their secretome, in addition to pro-inflammatory cytokines, angiogenic growth factors, and ECM, has strong impact on the formation, stabilization, and remodeling of vasculature. Their capacity for differentiation further contributes to vascular remodeling in different manners. Pericytes have several interactions with different components of the TME, such as composing the pre-metastatic niche, endorsing cancer cells growth, enhancing drug resistance through paracrine activity, and activating M2 macrophage polarization

48–49

Immune cells

TAMs

Macrophages are myeloid lineage cells of the innate immune system arising from bone marrow-derived monocytic progenitor cells that differentiate into tissue macrophages, bone resorbing osteoclasts, and antigen-presenting dendritic cells. Macrophages are critical to maintain tissue homeostasis and protection against infectious agents through phagocytosis, cell engulfment, and clearance of cellular debris. In cancer cells these functions are frequently inhibited and the TAM population consists of tissue-resident macrophages as well as monocyte-derived cells, which are recruited from the circulation to the TME. TAMs are present in high numbers in the TME and exert an immuno-modulatory effect by secreting diverse factors such as cytokines and chemokines

50–52

T-Cells

T-cells play a central role in the adaptive immune response and present a T-cell receptor (TCR) on their cell surface. T-cells produce cytokines to regulate other types of immune cells. Their immune-mediated cell death is exerted by two major subtypes: CD4 + helper T-cells, which function by activating memory B cells and cytotoxic T cells, resulting in a larger immune response; and CD8 + killer T cells, which are cytotoxic and therefore are able to directly kill cancer cells. Other types of T-cells include regulatory T-cells (Tregs), which provide the critical mechanism of tolerance whereby immune cells are able to distinguish invading cells from “self”; and γδ T-cells, which regulate immunosuppressive functions of IELs and also play roles in development of tolerance

53–56

B-Cells

B-cells function in the humoral immunity component of the adaptive immune system and secrete antibody molecules. Antigen-activated memory B-cells proliferates and differentiates into an antibody-secreting effector cell called plasma cell or plasmablast. B-cells present antigens and secrete cytokines. B-cells maturation occur in the bone marrow. There is increasing evidence that tumour-infiltrating B-cells and plasma cells, jointly referred to as tumour-infiltrating B-lymphocytes (TIL-Bs), play a critical synergistic role in cancer control. TIL-Bs endorse anticancer immunity through their antigen presentation to T-cells, and their role in assembling and perpetuating immunologically “hot” TMEs involving T-cells, NK cells, and myeloid cells

57–58

NK Cells

NK cells, which are defined as CD3- CD56 + cells in humans, are cytotoxic lymphocyte belong to the innate immune system and protect the host by killing stressed, infected, or transformed cells. NK cells orchestrate anticancer immune responses via cellular cross-talk. NK cells are a plastic and heterogenous population allowing them to gain diverse phenotypes dependent on the signaling cues or tissue context to which they are exposed. Differently from T-cells, NK cells require no tumour-specific recognition and are not limited by MHC inhibition. The widespread anticancer effects and relative therapeutic safety of NK cells, which directly detect and destroy cancer cells, make them promising candidates for cancer immunotherapy

59–60

MDSCs

MDSCs are heterogeneous activated immature cells from the myeloid lineage and are an important component of immunosuppressive networks. MDSCs can interact with T-cells, NK cells, macrophages, and DCs to regulate their functions. MDSCs potently inhibit T-cell activity contributing to the immune escape of cancer. Immature MDSCs with remarkable immunosuppressive activity accumulate during tumor development and endorse tumor progression through supporting cell survival, invasion, metastases and angiogenesis. High levels of MDSC in the TME correlate with lower survival of patients with solid tumors. Targeting MDSCs may be a promising strategy for immunotherapy, modifying the immunosuppressive microenvironment and augmenting the efficiency of tumor immunotherapy

61–62

TANs

Neutrophils are myeloid derived white circulating cells in blood and are primarily involved in the human innate immunity against pathogens. TANs promote cancer progression and metastasis through communication with other immune cells, multiple growth factors, inflammatory factors, and chemokines, which together establish an immunosuppressive TME. The function of TANs in tumor has been the subject of contradicting reports pointing toward a dual role played by them in cancer progression. Indeed, upon cytokine stimulation, TANs acquire the potentiality to polarize to antitumor (N1) or pro-tumor (N2) phenotype: N1 TANs are characterized by high levels of an TNFα, ICAM-1, CCL3, and low levels of Arginase axis, whereas N2 TANs are defined by upregulation of chemokines CCL2-CCL4, CCL8, CCL12, CCL17, CXCL1, CXCL2, CXCL8 and CXCL16

63–64

DCs

DCs orchestrate anticancer immune responses and are impaired in tumor patients. DCs continuously scan and protect the environment for danger signals in an immature state. DCs become activated, mature, and trigger anticancer immune responses in presence of tumor antigens and danger signals. Thus, DCs possess the unique capacity to act as messengers between the innate and the adaptive immune systems by cross-presenting antigens and priming T-cells. DCs become regressed into an immature state, compromising their ability to activate T-cells, resulting in T-cell anergy, Treg recruitment, and thus fostering cancer tolerance, in an immunosuppressive tumor environment. Dysfunctional DCs are implicated in immune evasion, cancer growth, metastasis initiation, and cancer treatment resistance

65–66

ECM

ECM

The ECM is one of the main components of cancer exerting important functions such as modulating the microenvironment, providing mechanical support, and serving as a source of signaling molecules. The quantity of ECM components are primary factors determining tissue stiffness. During carcinogenesis, the interplay between tumor cells and the TME frequently leads to the stiffness of the ECM, resulting in aberrant mechanotransduction and further malignant transformation. In cancer, several components of the ECM are subject to alterations which are mainly due to increased or reduced quantity of the ECM components, as well as changes in the function of ECM molecules. These alterations can be induced either indirectly by TME cells with CAFs being of particular interest in this regard, or directly by the cancer cells

67–68

Secreted Molecules

ECVs

ECVs are secreted by all types of cells, are protected by a lipid bilayer, and contain proteins, lipids, and/or RNAs. ECVs play a critical role in intercellular communications. ECVs can induce angiogenesis and ECM remodeling, impact on tumor cell proliferation, establish pre-metastatic niches, endorse cancer metastasis, and inhibit immune response. ECVs can contribute to the crosstalk among tumor, immune, stromal, and endothelial cells to provide TME diversity. ECV components can be locally delivered to the TME and/or transferred to distant sites to direct cancer behaviour. Thus, ECVs as carriers possess the important capacity to shuttle regulatory molecules between tumor cells and multiple stromal cells, producing significant phenotypic alterations in the TME

69–70

GFs

GFs act as cellular signaling factors to regulate numerous processes such as cell growth, function, differentiation, and metabolism. GFs play a key role in regulating important processes in healthy cells, and affect tumor growth and progression in cancer cells. The primary communication between tumor cells and their microenvironment is through GFs and receptors for these molecules. A growth factor binds to its cell-surface receptor and initiates intracellular signal cascades that results in the modulation of gene expression. Both epithelial and mesenchymal cells produce growth factor into the microenvironment. Hence, abnormal cellular responses to GFs are underly malignant transformation. The most common GFs in the TME are EGFs, PDGFs, IGFs, FGFs, VEGFs, and TGF-β

71–72

Hormones

Hormones act as cellular signaling factors to regulate several processes such as cell growth, function, differentiation, function, and metabolism in healthy cells. Hormones exert their functions by binding to specific receptors on target cells to induce a downstream signal transduction pathway that typically activates gene transcription, leading to increased expression of target proteins, which can enhance or suppress the aforementioned processes. Hormones also mediate the interplay between tumor cells, their interaction with the ECM, and other cells of surrounding tissues. These complex interactions remarkably affect tumor growth, tumor progression, and angiogenesis in cancer cells. Hormone-induced modulation affects several cell types within the TME, including CAFs and TILs, which interplay with cancer cells

71, 73

Cytokines

Cytokines are small proteins important in cell signaling. Cytokines are produced by a broad range of cells and include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors. Cytokines are responsible for the pleiotropic actions in tumor such as growth, EMT, angiogenesis, leukocyte infiltration, and therapy resistance. The TME directly affects tumor progression and invasion by synthesizing different cytokines. Several pro-inflammatory cytokines, including IFN-γ, TNFα, TGF-β, and ILs contribute to the initiation, progression, and metastasis in cancer. Cytokines present in the TME can have a dual role, since they can show both a pro-inflammatory and anti-inflammatory potential, driving infiltration and inflammation, and also endorsing evasion of immune system and pro-tumoral effects

74, 32

Chemokines

Chemokines are a family of small cytokines or signaling proteins secreted by cells that activate directional movement of leukocytes and other cells. Chemokines are important for biological processes such as morphogenesis, wound healing and cancers. Chemokines are responsible for the pleiotropic actions in tumor such as growth, EMT, angiogenesis, leukocyte infiltration, and therapy resistance. Chronic inflammation is also an instructive process of tumor progression, where chemokines are spatio-temporally secreted by cancerous cells and leukocyte subtypes that trigger cell trafficking into the TME. Chemokines present in the TME can have a dual role, since they can display both a pro-inflammatory and anti-inflammatory potential, driving infiltration and inflammation, and also supporting evasion of immune system and pro-tumoral effects

74–75