Skip to main content
Download PDF

Targeting Endocytosis  and Cell Communications  in the Tumor Immune Microenvironment

Cell Communication and Signaling volume 20, Article number: 161 (2022) Cite this article

Abstract

The existence of multiple endocytic pathways is well known, and their exact biological effects in tumors have been intensively investigated. Endocytosis can affect the connection between tumor cells and determine the fate of tumor cells. Many relationships between endocytosis and tumor cells have been elucidated, but the mechanism of endocytosis between different types of cells in tumors needs to be explored in greater depth. Endocytic receptors sense the environment and are induced by specific ligands to trigger communication between tumor and immune cells. Crosstalk in the tumor microenvironment can occur through direct contact between cell adhesion molecules or indirectly through exosomes. So a better understanding of the endocytic pathways that control cell adhesion molecules and function is expected to lead to new candidates for cancer treatment. In additional, tumor-derived exosomes may changes immune cell function, which may be a key role for tumors to evade immune detection and response. The overall understanding of exosomes through endocytosis is also expected to bring new candidates for therapeutic regulation of tumor immune microenvironment. In this case, endocytic pathways coordinate cell adhesion molecules and exosomes and can be used as targets in the tumor immune microenvironment for cancer treatment.

Video Abstract

Background

Endocytosis refers to the formation of 60–120 nm vesicles through invagination of the plasma membrane, which wraps and imports foreign substances into cells to regulate the internalization of substances (liquid and extracellular components, such as proteins, lipids, metabolites, small molecules and ions), signal transduction and composition [1,2,3]. The endocytic pathway integrates various signals to promote the development of cells. Receptor-mediated signal transduction can be regulated by endosome sorting, which effectively isolates the receptor from cytoplasmic effectors and promotes proteolysis. Receptor-related processes are more closely related to phosphorylation [4] and ubiquitination levels [5].

The well-known effects of endocytosis is necessary for a diverse range of morphogenetic and dynamic tissue events. Endocytosis can cause changes in tissue morphology through various processes, such as signal transduction and effects on the cytoskeleton [6]. Similarly, asymmetric division caused by endocytic transport is an important target for manipulating stem cells that lead to tumor recurrence [7]. In addition, endocytosis and different types of cells intertwine to play a decisive role in the tumor microenvironment (TME). The crosstalk in the tumor microenvironment can occur directly through cell-to-cell contact between cell adhesion molecules or indirectly through extracellular vesicles. Immune cells, including specialized antigen-presenting cells and natural killer cells, rely on endocytosis to quickly gather receptors to detect targets on tumor cells for antigen presentation [8]. Exosomes target specific types of recipient cells, and the exchange of information between cells also involves endocytosis [9]. Therefore, endocytosis mediates the communication between tumor cells and immune cells and coordinates the interaction between different types of cells to control the tumor immune microenvironment (Fig. 1). We review and clarify the role of endocytosis in tumor cells and the latest developments in communication in the tumor microenvironment.

Fig. 1
figure 1

Cell-to-cell communication through direct and indirect contact. Crosstalk in the tumor microenvironment can be through direct contact between adhesion molecules, or indirectly through secretion signals from extracellular vesicles. Tumor surface antigen regulation and tumor-induced immune suppression involve endocytic pathway in tumor immunity. In addition, immunosuppression may arise through accumulating and secreting exosomes around tumor

Full size image

Progression of endocytosis in tumor cells

Studies in the past decade have shown that the functional interaction between cell signaling and endocytosis is important at all stages of morphogenesis and regulating cell proliferation, metabolism, movement, differentiation and immunity [10]. Cells sense the environment and each other through activation of cell surface signal receptors induced by ligands. Among them, tyrosine kinase receptor (RTK) and G protein-coupled receptor (GPCR) participate in homeostatic regulation to prevent ligand-induced overactivation of downstream effectors. This paradigm has also been extended to other receptors, including transforming growth factor (TGFβ) and cytokines. In addition, Notch and Wnt coordinate the fate of adjacent tumor cells through endocytosis, highlighting the influence of cell morphology on fate [11, 12]. Endocytosis seems to be the simplest way to regulate cell signal transduction by controlling the number of activated receptors. The activation of receptors or downstream effectors usually stimulates endocytosis, but questions remain about endocytosis and signal transduction under in vivo conditions. Endocytosis and signal transduction seem to be two aspects of the same coin, raising the question of whether the same biochemical pathway can achieve different biological results. Similarly, given that the high overlap between pathways is activated by multiple signal receptors, can the detection mechanism on the cell membrane break down many input signals into specific signals?.

The increasing understanding of the link between endocytosis and signal transduction raises the possibility that targeted interference with endocytosis may alter disease-related phenotypes, especially those related to abnormal cell specifications. The endocytosis mechanism in tumor heterogeneity may be the basis of the specific characteristics of tumors and their level of sensitivity to therapeutic drugs targeting signal receptors [13]. The dynamic balance in tissues strongly depends on the interaction between cells and the extracellular matrix [14]. In contrast, integral proteins can regulated the extracellular matrix (ECM) and transmit signals between the cell and its surroundings [15].

In the past decades of research, the main focus has been on studies related to endocytosis and signaling pathways. With a better understanding of the tumor immune microenvironment, the relationship between tumor cells and immune cells is now recognized, and endocytosis mediates cell-to-cell communication through the regulation of direct or indirectly contact. Therefore, we discuss in depth about endocytosis mediating tumor immune microenvironment through regulation of cell adhesion molecules (including major histocompatibility complex (MHC), immune checkpoints) and exosomes.

Endocytosis mediates tumor immune microenvironment through cell adhesion molecules

Endocytosis and tumor immune microenvironment

The overall complexity of tumors presents challenges to the development of effective anticancer treatments [16,17,18]. In the process of tumor development, tumor heterogeneity intensifies as tumor cells and noncellular components of the tumor microenvironment (TME) mature [19, 20]. The TME consists of extracellular matrix (ECM), stromal cells (such as fibroblasts, mesenchymal stromal cells, pericytes, occasionally fat cells, blood and lymphatic network) and immune cells (including T and B lymphocytes, natural killer cells, macrophages) [21]. Tumor immune escape refers to the ability of tumor cells to avoid recognition and attack by the immune system. It is an important strategy for tumor survival and development [22]. Tumor surface antigen regulation and tumor-induced immune suppression involve the endocytic pathway in tumor immunity.

The cells of the innate immune system, such as monocytes, macrophages and dendritic cells (DCs)—are specialized antigen-presenting cells. In addition to this natural killer cells (NKs) rely on recognition of receptors and other cell surface molecules to rapidly detect microbial proteins or membrane molecules on tumor cells to orchestrate downstream inflammatory responses [23]. Key to the bridging role between innate and adaptive immunity is the processing and cross-presentation of antigens by APCs to T cells. The ability of APCs to engulf tumor cells through phagocytosis, a process that involves target cell recognition, phagocytosis and lysosomal digestion, is regulated by receptor-ligand interactions. Although healthy normal tissues and cells inherit the ability to avoid self-clearance by phagocytosis by expressing anti-phagocytic molecules, cells are more dependent on similar mechanisms to evade immune eradication [24, 25]. Thus identifying and targeting phagocytic checkpoints in cancer will provide a new avenue to develop cancer immunotherapies to eliminate tumor immune escape.

More and more phagocytic checkpoints are found to play an essential role in innate and adaptive immunity. Phagocytic checkpoint blockade, including anti-CD47 therapy and PD-L1 blockade, stimulates the innate and adaptive immune systems to generate anti-tumor responses, combining them with existing cancer immunotherapy strategies to improve the response rate to tumor treatment [26]. When major signaling pathways are constitutively activated by genetic disorders, such as v-Src or mutated K-Ras, a receptor-independent pattern of macropinocytosis occurs. Macropinocytosis provides tumor cells with an additional means of acquiring nutrients and internalizing adhesions molecules to support their growth and spread. By inhaling and concentrating amino acids and proteins in the extracellular fluid, tumor cells activate the mammalian target of rapamycin 1 (mTORC1) to stimulate transcriptional translation and support growth [27]. Thus, endocytosis inhibitors as well as immune checkpoint blockade therapy offer promise for clinical trials in a wide range of tumors, and can be used in combination with other monoclonal antibodies or immune checkpoint inhibitors (Table 1).

Table 1 Categorization and features of endocytosis process
Full size table

Endocytosis and cell adhesion molecules

The differentiation of initial T cells into effector cells can promote the killing of cancer cells. This effect occurs when the T-cell receptor (TCR) triggered by the signal accumulates, and then specific antigen presenting cells (APCs) are recognized [28]. The imbalance of endocytic events that control TCR circulation and degradation has been considered an important determinant of antigen presentation by immune cells. TCR is a protein complex formed by an antigen recognition module composed of α and β chains and a signal transduction module composed of ζ chain homodimers and CD3 chain clusters [29].

At present, clathrin-dependent and clathrin-independent endocytosis have been identified as the main pathways involved in the internalization of TCR [30]. Postendocytosis receptor movement is coordinated by ubiquitinated Rab GTPases, SNARE and regulators and effectors of endosomal subpopulations [31, 32]. The cargo can be recovered directly from early endosomes (ESEs) via a rapid, microtubule-independent process is achieved by rabenosyn5, which is the Fab 1, YOTB, Vac 1 and EEA1 (FYVE) domain containing Rab5 and Rab4 effectors [33]. Internalized receptors are incorporated into endosomes and can also be delivered to the plasma membrane through a slow, microtubule-dependent pathway [34]. In addition to the universal Rabs, Rab3d, Rab8a, Rab8b, Rab29, Rab35, intraflagellar transport (IFT), and electrohydrodynamic (EHD) family proteins act sequentially in this pathway based on the ability to recycle TCRs [35,36,37]. Rab8 has been identified as the terminal pathway. It recruits v-SNARE VAMP3 and t-SNARE SNAP23 synaptic fusion protein to finally allow the recovered TCR to be fused to the cell membrane [36]. T cells can also enhance the release of extracellular vesicles (EVs) through stimulation, such as TCR triggering or T-cell activation [38, 39]. Activated T cells release biologically active Fas ligand and APO2 ligand in EVs, thereby promoting activation and inducing cell death [40]. In addition, the EVs formed by CD8+ CTL MVBs contain granzyme and perforin [41] (Fig. 2).

Fig. 2
figure 2

Regulation of immune response by exosomes. Exosomes from distinct cellular sources, including immune cells (B cell, T cell, macrophage, and dendritic cells) and cancer cells, exosomes with cargos that can influence the proliferation and activity of recipient cells of both the innate and adaptive immune system

Full size image

To achieve complete activation, B cells rely on their ability to capture external antigens and present them to CD4+ T cells as peptide fragments loaded on major histocompatibility complex class II (MHC II) molecules [42]. This interaction differentiates B cells into plasma cells that produce high affinity and develop into memory B-cell populations [43]. Regarding the mechanism by which B cells extract antigens on the cell surface, one view is that local lysosomes secrete and release proteases and acidify the synaptic cleft of related antigens to facilitate their extraction of antigen [44]. Another view is that the tension exerted on the synaptic membrane mediated by myosin II-A triggers internalization of the antigen into coated clathrin [45].

The binding of surface antigens to the B-cell receptor (BCR) triggers the recruitment of PAR3 to the antigen contact site, which leads to polarization of the microtubule network, in which the centrosome transfers to the immune synapse in a Cdc42-dependent manner [44, 46]. Centrosome relocation directs the recruitment of MHC II+ lysosomes, which can fuse with antigen-containing endosomes to facilitate antigen processing. It is worth noting that the Lamp1+ multivesicular compartment, which contains both antigen and MHC molecules, has been found to be closely related to the immune synapse of activated B lymphocytes [44]. Therefore, determining the specific mechanism used to selectively enhance the extraction of antigens by B cells to enhance the activation of T cells should be the focus of future research.

Immunosuppression involves inducing the expression of immunosuppressive molecules or their receptors, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T cell immunoglobulin and mucin domain 3 (TIM-3), Indoleamine 2,3-dioxygenase (IDO), V-domain Ig inhibitor of T-cell activation (VISTA), killer cell immunoglobulin-like receptors (KIR), T cell immunoglobulin and ITIM domain (TIGIT), B and T lymphocyte attenuator (BTLA) and Lymphocyte activation gene-3 (LAG-3), which are called immune checkpoints and can inhibit the activated lymphocytes of effector T cells and ultimately lead to tumor immune escape [47]. Immune checkpoints are also specifically expressed on protumor immune cells (e.g., Tregs). For example, PD-1 on T effectors reduces activation, while PD-1 on Tregs enhances immunosuppressive effects. In addition, linker for activation of T cells (LAT) [48, 49] and lymphocyte-specific protein tyrosine kinase (LCK) [50, 51], with the assistance of specific vesicle-related proteins, ensure the optimal TCR level required for T-cell activation. Changes in endocytic transport are associated with cancer, so a better understanding of the endocytic pathways that control immune checkpoints and function is expected to lead to new candidates for cancer treatment.

Endocytosis mediates tumor immune microenvironment through exosomes

Endocytosis and exosomes

In addition, immunosuppression may arise through the accumulation and secretion of exosomes around tumors. Exosomes can inactivate cytotoxic T lymphocytes (CTLs) to enhance the immune tolerance of tumor cells [52,53,54,55]. The communication between cancer cells and surrounding cells is a bidirectional process that involves multiple mechanisms. Crosstalk in the tumor microenvironment can occur directly through contact between antigen presentation or indirectly through secretion signals from extracellular vesicles. Therefore, the therapeutic method of regulating cell-to-cell communication by endocytosis may be a promising strategy in the fight against tumors.

Liquid and extracellular components (such as proteins, lipids, metabolites, small molecules and ions) can enter cells through endocytosis and plasma membrane invagination, along with cell surface proteins [56]. Tumor-derived exosomes are bound and internalized by organ-specific cells. Heparan sulfate proteoglycans mediate the interaction between cells and exosomes. Exosome transfer to the recipient cell can be competitively blocked by heparinoids because heparin is structurally similar to heparan sulfate [57]. The plasma membrane bud formed on the side of the cell cavity has an orientation from outside to inside, which leads to the formation of the ESE (early endosome) [58]. The ESE can also be fused with the ER (endoplasmic reticulum) and anti-Golgi network (TGN), which may explain why the phagocytic cargo contains components of the ER, TGN and mitochondria, and the ESE may contain membrane and intraluminal components representing different origins [58]. MVBs are formed by the inward invagination of the late endosome restriction membrane (that is, the two invaginations of the plasma membrane). MVBs contain multiple intraluminal vesicles (ILVs), which lead to exosomal cargo in future modifications. As part of the formation of ILVs, proteins (originally located on the cell surface) can be clearly distributed between ILVs [56]. MVBs can be fused with autophagosomes, and the final content will be degraded in the lysosome, allowing the degradation products to be recovered by the cell. MVB that does not follow this trajectory is transported to the plasma membrane through the cell cytoskeleton and microtubule network and is docked on the lumen side of the plasma membrane with the help of MVB docking protein to cause exocytosis [59]. Rabs, endosomal sorting complex required for transport (ESCRT) and other related proteins (CD9, CD81, CD63, TSG101, Alix, and putative universal biomarker of syntenin-1) are used as exosomal markers or are related to the biogenesis of exosomes [58, 60] (Fig. 3).

Fig. 3
figure 3

Regulation of immune response by exosomes. Exosomes from distinct cellular souurces, including immune cells (B cell, T cell, Macrophage and Dendritic cells) and cancer cells, exosomes with cargos than can influence the proliferation and activity of recipient cells of both the innateand adaptive immune system

Full size image

Exosomes can also contain different types of cell surface proteins, intracellular proteins, RNA, DNA, amino acids and metabolites [56]. The questions surrounding the function of exosomes focus mainly on understanding the fate of their components and their induction of phenotypic and molecular changes in recipient cells. The uptake and secretion pathways of exosomes may intersect, resulting in a mixed population of endogenously produced and circulating exosomes produced over time. The unique mechanisms and pathways related to the uptake of exosomes [58, 61], as well as the specificity of exosomes for certain cell types, increase the functional complexity of exosomes in cell-to-cell communication.

Exosomes are vesicles with membrane structures between 40 and 160 nm (both 100 nm) in diameter [9, 62, 63] containing RNA, proteins and lipids that play a role in tumor proliferation, metastasis, immunosuppression and drug tolerance [58, 61]. These processes seem to be similar to leukocyte transendothelial migration, in which integrins are involved in the adhesion/attachment of exosomes to receptor cells, followed by the enrichment of four transmembrane microstructural domains facilitating exosome fusion [64,65,66,67]. The endocytosis of exosomes is the most important way they deliver content. It can be divided into micropinocytosis [68, 69], phagocytosis [70], clathrin-mediated endocytosis [71], caveolin-mediated endocytosis [72] and clathrin/caveolin-independent endocytosis [73]. The endocytosis of exosomes depends on the actin cytoskeleton, phosphatidylinositol 3-kinase (PI3K) and dynamin2 [70]. Studies have shown that the pharmacological inhibitors EIPA and LY294002 inhibit Na+-H+ ion exchange and PI3K activity, which can inhibit the effect of macropinocytosis and reduce the uptake of exosomes [74]. Clathrin-dependent endocytosis uses clathrin and AP2 to cover the membrane and induce exosomes to invade vesicles; clathrin/cavolin-independent endocytosis is caused by RhoA, Cdc42 and Arf6 [75].

Exosomes targeting recipient cells by endocytosis have been confirmed in tumors. For example, oncogenic signals induced by KRAS mutation expression promote exosomal uptake in human pancreatic cancer cells through micropinocytosis [2, 76] and promote the uptake of exosomal cargo by human melanoma cells by fusion with the plasma membrane [77]. Exosomes derived from rat adrenal medulloma PC12 cells are more likely to rely on clathrin-dependent endocytic uptake [74]. It is possible that internalized exosomal cargo varies depending on the endocytosis and the recipient cell status that regulates uptake of extracellular molecules and vesicles.

Exosomes in tumor progression and metastasis

The discovery of exosomes, especially their role in mediating the transportation or “trafficking” of biological materials, has explained various pathological and physiological phenomena that involve the transmission of information between cells [78]. As a new model for mediating information exchange between cells, exosomes transport oncogene message during the occurrence and development of tumors. Recent studies have elaborated on the important role of exosomes in tumor carcinogenesis [76]. Tumor-derived exosomes can promote tumor formation by regulating the synthesis of cell-independent ncRNA [79]. During the development of cancer, there is competition between cancer cells and neighboring normal cells [80]. As a homeostatic mechanism, abundant noncancer cells can release tumor suppressor miRNAs, thereby suppressing the malignant phenotype of adjacent cancer cells [81,82,83,84,85,86]. In addition, it has been reported that differences in exosome content can distinguish several types of cancer cells (such as prostate cancer, gastric cancer, and laryngeal squamous cell carcinoma) from normal cells [87].

Exosomal RNA derived from tumor cells can enhance the proliferation, migration and tube formation of endothelial cells, thereby promoting tumors and lymphatic vasculature [88,89,90,91,92,93]. Proteomic analysis of exosomes showed that the integrin expression pattern of cancer cells contributes to the tendency of metastasis [94]. For example, integrin α6β4 and α6β1 are related to lung metastasis, and integrin αvβ5 is related to liver metastasis [95]. Depletion of integrins α6β4 and αvβ5 reduced exosomal uptake and resulted in the inhibition of lung and liver metastasis, respectively. Therefore, the integrins found on specific tumor-derived exosomes can be used to predict organ-specific cancer metastasis and are a new target for the development of cancer metastasis treatment strategies [96,97,98,99].

Exosomes regulate cancer immunology

In most studies, the recipient cells of tumor derived exosomes are cancer-related immune cells and other stromal cells, which dynamically regulate each other in the tumor microenvironment [100]. Compared with studying the role of exosomes in other types of cells, research on tumor related exosomes is progressing rapidly. More and more evidence supports the complex intercellular communication mediated by exosomes in tumor immune microenvironment. Tumor-derived exosomes content HSP72 can trigger myeloid-derived inhibitory cell activation through STAT3 [101]. Tumor exosomes block the maturation and migration of dendritic cells in a PD-L1 dependent manner [102]. The tumor-derived exosomal DNA by circulating neutrophils can enhance the production of tissue factor and IL-8, thereby promoting tumor inflammation and thrombosis [103]. Therefore, tumor-derived exosomes may changes immune cell function, which may be a key role for tumors to evade immune detection and response.

Similarly, exosomes released by immune cells affect tumor development by regulating immune response [104]. Exosomes released by NK cells show FasL membrane expression, and produce strong cytotoxicity to cancer by eliminating Fas + tumor cells [105]. In addition, in patients with acute myeloid leukemia (AML), plasma exosomes carrying leukemia-related antigens and a variety of inhibitory molecules can inhibit tumor activity by interfering with NK-92 cells [106]. NK-92 cell-derived exosomes TNF-α have cytotoxic effects on melanoma cells and block cell proliferation signaling pathways [107]. In a phase II trial, IFN-γ mature DC-derived exosomes loaded with MHC class peptides can enhance NK cell activity in patients with non-small cell lung cancer (NSCLC) [108]. T cells can also transfer CD40L to B cells through helper T cells [109]. The binding of antigen-loaded B cells to specific CD4+ T cells stimulates the release of EVs with peptide MHC-II complexes, which directly stimulate naive CD4+ T cells [110] (Fig. 3). In addition, ovalbumin (OVA)-stimulated dendritic cell exosomes are more effective than microvesicles to trigger antigen (OVA)-specific CD8+ T cell activation [111].

Conclusion

The field of communication in the tumor microenvironment is a relatively new concept in tumor biology and rapidly evolving. Cancer-stromal crosstalk is an extremely complex phenomenon, and different forms of cellular communication are highly expressed in cancer and clearly involved in cancer development. Different forms of cell communication are highly expressed in cancer and obviously participate in the occurrence of cancer. With our in-depth exploration and understanding of the connection of endocytosis, we believe that the communication between cells is essential for the creation of tumor niches. Therefore, a novel medical method focuses on inhibiting cell-to-cell communication in cancer, or using these communication methods as a vehicle for delivering drugs to tumor cells. Immune cells can rely on endocytosis to mediates cell adhesion molecules quickly detect targets on tumor cells. The overall understanding of exosomes through endocytosis is also expected to bring new candidates for therapeutic regulation of tumor immune microenvironment. Therefore, further research is needed to fully understand endocytosis and clarify possible specific targets to inhibit tumors.

Availability of data and materials

Not applicable.

Abbreviations

TME:

Tumor microenvironment

ILVs:

Intraluminal vesicles

RTK:

Tyrosine kinase receptor

GPCR:

G protein-coupled receptor

TGFβ:

Transforming growth factor

ECM:

Extracellular matrix

TCR:

T cell receptor

BCR:

B cell receptor

MHC:

Major histocompatibility complex

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

PD-1:

Programmed cell death protein 1

TIM-3:

T cell immunoglobulin and mucin domain 3

IDO:

Indoleamine 2,3-dioxygenase

VISTA:

V-domain Ig inhibitor of T-cell activation

KIR:

Killer cell immunoglobulin-like receptors

TIGIT:

T cell immunoglobulin and ITIM domain

BTLA:

B and T lymphocyte attenuator

LAG-3:

Lymphocyte activation gene-3

CTL:

Cytotoxic T lymphocytes

Treg cells:

Regulatory T cells

MDSC:

Marrow-derived suppressor cells

DC:

Dendritic cells

NK:

Natural killer

mTORC1:

Mammalian target of rapamycin 1

APC:

Antigen presenting cells

ESE:

Early endosome

FYVE:

Fab 1, YOTB, Vac 1 and EEA1

IFT:

Intraflagellar transport

EHD:

Electrohydrodynamic

LCK:

Lymphocyte-specific protein tyrosine kinase

LAT:

Linker for activation of T cells

EVs:

Extracellular vesicles

MVBs:

Multivesicular bodies

ER:

Endoplasmic reticulum

TGN:

Anti-Golgi network

ESCRT:

Endosomal sorting complex required for transport

PI3K:

Phosphatidylinositol 3-kinase

PS:

Phosphatidylserine

FasL:

Fas ligand

AML:

Acute myeloid leukemia

NSCLC:

Non-small cell lung cancer

OVA:

Ovalbumin

SC:

Stem cell

IC:

Immune checkpoint

MSI-H:

Microsatellite instability

dmmR:

DNA mismatch repair defect

HLA-B:

Human leukocyte antigen B

CEACAM-1:

Carcinoembryonic antigen cell adhesion molecule 1

PVR:

Poliovirus receptor

References

  1. Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature. 2003;422:37–44.

    Article  CAS  PubMed  Google Scholar 

  2. Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, Grabocka E, Nofal M, Drebin JA, Thompson CB, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497:633–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Germain RN. An innately interesting decade of research in immunology. Nat Med. 2004;10:1307–20.

    Article  CAS  PubMed  Google Scholar 

  4. Wallroth A, Haucke V. Phosphoinositide conversion in endocytosis and the endolysosomal system. J Biol Chem. 2018;293:1526–35.

    Article  CAS  PubMed  Google Scholar 

  5. Piper RC, Dikic I, Lukacs GL. Ubiquitin-dependent sorting in endocytosis. Cold Spring Harb Perspect Biol. 2014;6:a016808.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Nino CA, Sala S, Polo S. When ubiquitin meets E-cadherin: plasticity of the epithelial cellular barrier. Semin Cell Dev Biol. 2019;93:136–44.

    Article  CAS  PubMed  Google Scholar 

  7. Polo S, Di Fiore PP. Endocytosis conducts the cell signaling orchestra. Cell. 2006;124:897–900.

    Article  CAS  PubMed  Google Scholar 

  8. Chao MP, Weissman IL, Majeti R. The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol. 2012;24:225–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020. https://doi.org/10.1126/science.aau6977.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sorkin A, von Zastrow M. Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol. 2009;10:609–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lloyd-Lewis B, Mourikis P, Fre S. Notch signalling: sensor and instructor of the microenvironment to coordinate cell fate and organ morphogenesis. Curr Opin Cell Biol. 2019;61:16–23.

    Article  CAS  PubMed  Google Scholar 

  12. Clara JA, Monge C, Yang Y, Takebe N. Targeting signalling pathways and the immune microenvironment of cancer stem cells–a clinical update. Nat Rev Clin Oncol. 2020;17:204–32.

    Article  PubMed  Google Scholar 

  13. Mosesson Y, Mills GB, Yarden Y. Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer. 2008;8:835–50.

    Article  CAS  PubMed  Google Scholar 

  14. Shapiro L, Weis WI. Structure and biochemistry of cadherins and catenins. Cold Spring Harb Perspect Biol. 2009;1:a003053.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hamidi H, Ivaska J. Every step of the way: integrins in cancer progression and metastasis. Nat Rev Cancer. 2018;18:533–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu J, Dang H, Wang XW. The significance of intertumor and intratumor heterogeneity in liver cancer. Exp Mol Med. 2018;50:e416.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Grzywa TM, Paskal W, Wlodarski PK. Intratumor and intertumor heterogeneity in melanoma. Transl Oncol. 2017;10:956–75.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mroz EA, Rocco JW. Intra-tumor heterogeneity in head and neck cancer and its clinical implications. World J Otorhinolaryngol Head Neck Surg. 2016;2:60–7.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Stanta G, Bonin S. Overview on clinical relevance of intra-tumor heterogeneity. Front Med (Lausanne). 2018;5:85.

    Article  Google Scholar 

  20. Wang M, Zhao J, Zhang L, Wei F, Lian Y, Wu Y, Gong Z, Zhang S, Zhou J, Cao K, et al. Role of tumor microenvironment in tumorigenesis. J Cancer. 2017;8:761–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, Hu G, Sun Y. New horizons in tumor microenvironment biology challenges and opportunities. BMC Med. 2015;13:45.

    Article  PubMed  PubMed Central  Google Scholar 

  22. He X, Xu C. Immune checkpoint signaling and cancer immunotherapy. Cell Res. 2020;30:660–9.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Morvan MG, Lanier LL. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer. 2016;16:7–19.

    Article  CAS  PubMed  Google Scholar 

  24. Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010;327:291–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer. 2004;4:11–22.

    Article  CAS  PubMed  Google Scholar 

  26. Jutras I, Desjardins M. Phagocytosis: at the crossroads of innate and adaptive immunity. Annu Rev Cell Dev Biol. 2005;21:511–27.

    Article  CAS  PubMed  Google Scholar 

  27. Florey O, Overholtzer M. Macropinocytosis and autophagy crosstalk in nutrient scavenging. Philos Trans Royal Soc B Biol Sci. 2019;374(1765):20180154.

    Article  CAS  Google Scholar 

  28. Sasmal DK, Feng W, Roy S, Leung P, He Y, Cai C, Cao G, Lian H, Qin J, Hui E, Schreiber H, Adams EJ, Huang J. TCR-pMHC bond conformation controls TCR ligand discrimination. Cell Mol Immunol. 2020;17(3):203–17.

    Article  CAS  PubMed  Google Scholar 

  29. Alcover A, Alarcon B, Di Bartolo V. Cell biology of T cell receptor expression and regulation. Annu Rev Immunol. 2018;36:103–25.

    Article  CAS  PubMed  Google Scholar 

  30. Compeer EB, Kraus F, Ecker M, Redpath G, Amiezer M, Rother N, Nicovich PR, Kapoor-Kaushik N, Deng Q, Samson GPB, et al. A mobile endocytic network connects clathrin-independent receptor endocytosis to recycling and promotes T cell activation. Nat Commun. 2018;9:1597.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Pfeffer SR. Rab GTPase regulation of membrane identity. Curr Opin Cell Biol. 2013;25:414–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhen Y, Stenmark H. Cellular functions of Rab GTPases at a glance. J Cell Sci. 2015;128:3171–6.

    CAS  PubMed  Google Scholar 

  33. de Renzis S, Sonnichsen B, Zerial M. Divalent Rab effectors regulate the sub-compartmental organization and sorting of early endosomes. Nat Cell Biol. 2002;4:124–33.

    Article  PubMed  Google Scholar 

  34. Patino-Lopez G, Dong X, Ben-Aissa K, Bernot KM, Itoh T, Fukuda M, Kruhlak MJ, Samelson LE, Shaw S. Rab35 and its GAP EPI64C in T cells regulate receptor recycling and immunological synapse formation. J Biol Chem. 2008;283:18323–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Soares H, Lasserre R, Alcover A. Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses. Immunol Rev. 2013;256:118–32.

    Article  CAS  PubMed  Google Scholar 

  36. Finetti F, Patrussi L, Masi G, Onnis A, Galgano D, Lucherini OM, Pazour GJ, Baldari CT. Specific recycling receptors are targeted to the immune synapse by the intraflagellar transport system. J Cell Sci. 2014;127:1924–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Onnis A, Finetti F, Patrussi L, Gottardo M, Cassioli C, Spano S, Baldari CT. The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis. Cell Death Differ. 2015;22:1687–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Blanchard N, Lankar D, Faure F, Regnault A, Dumont C, Raposo G, Hivroz C. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol. 2002;168:3235–41.

    Article  CAS  PubMed  Google Scholar 

  39. van der Vlist EJ, Arkesteijn GJ, van de Lest CH, Stoorvogel W, Nolte-‘t Hoen EN, Wauben MH. CD4(+) T cell activation promotes the differential release of distinct populations of nanosized vesicles. J Extracell Vesicles. 2012;1:18364.

    Article  Google Scholar 

  40. Monleon I, Martinez-Lorenzo MJ, Monteagudo L, Lasierra P, Taules M, Iturralde M, Pineiro A, Larrad L, Alava MA, Naval J, Anel A. Differential secretion of Fas ligand- or APO2 ligand/TNF-related apoptosis-inducing ligand-carrying microvesicles during activation-induced death of human T cells. J Immunol. 2001;167:6736–44.

    Article  CAS  PubMed  Google Scholar 

  41. Peters PJ, Borst J, Oorschot V, Fukuda M, Krahenbuhl O, Tschopp J, Slot JW, Geuze HJ. Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med. 1991;173:1099–109.

    Article  CAS  PubMed  Google Scholar 

  42. Welsh RA, Song N, Sadegh-Nasseri S. How does B cell antigen presentation affect memory CD4 T cell differentiation and longevity? Front Immunol. 2021;12:677036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mitchison NA. T-cell-B-cell cooperation. Nat Rev Immunol. 2004;4:308–12.

    Article  CAS  PubMed  Google Scholar 

  44. Yuseff MI, Reversat A, Lankar D, Diaz J, Fanget I, Pierobon P, Randrian V, Larochette N, Vascotto F, Desdouets C, et al. Polarized secretion of lysosomes at the B cell synapse couples antigen extraction to processing and presentation. Immunity. 2011;35:361–74.

    Article  CAS  PubMed  Google Scholar 

  45. Natkanski E, Lee WY, Mistry B, Casal A, Molloy JE, Tolar P. B cells use mechanical energy to discriminate antigen affinities. Science. 2013;340:1587–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Goldstein B, Macara IG. The PAR proteins: fundamental players in animal cell polarization. Dev Cell. 2007;13:609–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Toor SM, Sasidharan Nair V, Decock J, Elkord E. Immune checkpoints in the tumor microenvironment. Semin Cancer Biol. 2020;65:1–12.

    Article  CAS  PubMed  Google Scholar 

  48. Mingueneau M, Roncagalli R, Gregoire C, Kissenpfennig A, Miazek A, Archambaud C, Wang Y, Perrin P, Bertosio E, Sansoni A, et al. Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor. Immunity. 2009;31:197–208.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang W, Sommers CL, Burshtyn DN, Stebbins CC, DeJarnette JB, Trible RP, Grinberg A, Tsay HC, Jacobs HM, Kessler CM, et al. Essential role of LAT in T cell development. Immunity. 1999;10:323–32.

    Article  CAS  PubMed  Google Scholar 

  50. Ventimiglia LN, Alonso MA. The role of membrane rafts in Lck transport, regulation and signalling in T-cells. Biochem J. 2013;454:169–79.

    Article  CAS  PubMed  Google Scholar 

  51. Nika K, Soldani C, Salek M, Paster W, Gray A, Etzensperger R, Fugger L, Polzella P, Cerundolo V, Dushek O, et al. Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity. 2010;32:766–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang YA, Li XL, Mo YZ, Fan CM, Tang L, Xiong F, Guo C, Xiang B, Zhou M, Ma J, et al. Effects of tumor metabolic microenvironment on regulatory T cells. Mol Cancer. 2018;17:168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yu J, Du W, Yan F, Wang Y, Li H, Cao S, Yu W, Shen C, Liu J, Ren X. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol. 2013;190:3783–97.

    Article  CAS  PubMed  Google Scholar 

  54. Benencia F, Muccioli M, Alnaeeli M. Perspectives on reprograming cancer-associated dendritic cells for anti-tumor therapies. Front Oncol. 2014;4:72.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014;6:1670–90.

    Article  Google Scholar 

  56. Van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28.

    Article  PubMed  Google Scholar 

  57. Cerezo-Magaña M, Bång-Rudenstam A, Belting M. The pleiotropic role of proteoglycans in extracellular vesicle mediated communication in the tumor microenvironment. Semin Cancer Biol. 2020;62:99–107.

    Article  PubMed  Google Scholar 

  58. Mathieu M, Martin-Jaular L, Lavieu G, Thery C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9–17.

    Article  CAS  PubMed  Google Scholar 

  59. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). 2013;91:431–7.

    Article  CAS  Google Scholar 

  60. Kugeratski FG, Hodge K, Lilla S, McAndrews KM, Zhou X, Hwang RF, Zanivan S, Kalluri R. Quantitative proteomics identifies the core proteome of exosomes with syntenin-1 as the highest abundant protein and a putative universal biomarker. Nat Cell Biol. 2021;23:631–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. McKelvey KJ, Powell KL, Ashton AW, Morris JM, McCracken SA. Exosomes: mechanisms of uptake. J Circ Biomark. 2015;4:7.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Khan S, Jutzy JM, Aspe JR, McGregor DW, Neidigh JW, Wall NR. Survivin is released from cancer cells via exosomes. Apoptosis. 2011;16:1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.

    Article  CAS  PubMed  Google Scholar 

  64. Hemler ME. Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol. 2003;19:397–422.

    Article  CAS  PubMed  Google Scholar 

  65. Rana S, Zoller M. Exosome target cell selection and the importance of exosomal tetraspanins: a hypothesis. Biochem Soc Trans. 2011;39:559–62.

    Article  CAS  PubMed  Google Scholar 

  66. Mulcahy LA, Pink RC, Carter DR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014;3:24641.

    Article  Google Scholar 

  67. Chivet M, Javalet C, Laulagnier K, Blot B, Hemming FJ, Sadoul R. Exosomes secreted by cortical neurons upon glutamatergic synapse activation specifically interact with neurons. J Extracell Vesicles. 2014;3:24722.

    Article  PubMed  Google Scholar 

  68. Nakase I, Kobayashi NB, Takatani-Nakase T, Yoshida T. Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes. Sci Rep. 2015;5:10300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, Regen T, Hanisch UK, Simons M. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci. 2011;124:447–58.

    Article  CAS  PubMed  Google Scholar 

  70. Feng D, Zhao WL, Ye YY, Bai XC, Liu RQ, Chang LF, Zhou Q, Sui SF. Cellular internalization of exosomes occurs through phagocytosis. Traffic. 2010;11:675–87.

    Article  CAS  PubMed  Google Scholar 

  71. Barres C, Blanc L, Bette-Bobillo P, Andre S, Mamoun R, Gabius HJ, Vidal M. Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages. Blood. 2010;115:696–705.

    Article  CAS  PubMed  Google Scholar 

  72. Nanbo A, Kawanishi E, Yoshida R, Yoshiyama H. Exosomes derived from Epstein-Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells. J Virol. 2013;87:10334–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hazan-Halevy I, Rosenblum D, Weinstein S, Bairey O, Raanani P, Peer D. Cell-specific uptake of mantle cell lymphoma-derived exosomes by malignant and non-malignant B-lymphocytes. Cancer Lett. 2015;364:59–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tian T, Zhu YL, Zhou YY, Liang GF, Wang YY, Hu FH, Xiao ZD. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J Biol Chem. 2014;289:22258–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mayor S, Pagano RE. Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol. 2007;8:603–12.

    Article  CAS  PubMed  Google Scholar 

  76. Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, Lee JJ, Kalluri R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017;546:498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009;284:34211–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Dilsiz N. Hallmarks of exosomes. Future Sci OA. 2021;8(1):FSO764.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Melo SA, Sugimoto H, O’Connell JT, Kato N, Villanueva A, Vidal A, Qiu L, Vitkin E, Perelman LT, Melo CA, et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014;26:707–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kanada M, Bachmann MH, Contag CH. Signaling by extracellular vesicles advances cancer hallmarks. Trends Cancer. 2016;2:84–94.

    Article  PubMed  Google Scholar 

  81. Kosaka N, Yoshioka Y, Fujita Y, Ochiya T. Versatile roles of extracellular vesicles in cancer. J Clin Invest. 2016;126:1163–72.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Kosaka N, Iguchi H, Yoshioka Y, Hagiwara K, Takeshita F, Ochiya T. Competitive interactions of cancer cells and normal cells via secretory microRNAs. J Biol Chem. 2012;287:1397–405.

    Article  CAS  PubMed  Google Scholar 

  83. Han S, Gonzalo DH, Feely M, Rinaldi C, Belsare S, Zhai H, Kalra K, Gerber MH, Forsmark CE, Hughes SJ. Stroma-derived extracellular vesicles deliver tumor-suppressive miRNAs to pancreatic cancer cells. Oncotarget. 2018;9:5764–77.

    Article  PubMed  Google Scholar 

  84. Fonsato V, Collino F, Herrera MB, Cavallari C, Deregibus MC, Cisterna B, Bruno S, Romagnoli R, Salizzoni M, Tetta C, Camussi G. Human liver stem cell-derived microvesicles inhibit hepatoma growth in SCID mice by delivering antitumor microRNAs. Stem Cells. 2012;30:1985–98.

    Article  CAS  PubMed  Google Scholar 

  85. Zheng R, Du M, Wang X, Xu W, Liang J, Wang W, Lv Q, Qin C, Chu H, Wang M, et al. Exosome-transmitted long non-coding RNA PTENP1 suppresses bladder cancer progression. Mol Cancer. 2018;17:143.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Zhang H, Deng T, Ge S, Liu Y, Bai M, Zhu K, Fan Q, Li J, Ning T, Tian F, et al. Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7. Oncogene. 2019;38:2844–59.

    Article  CAS  PubMed  Google Scholar 

  87. Silva A, Bullock M, Calin G. The clinical relevance of long non-coding RNAs in cancer. Cancers (Basel). 2015;7:2169–82.

    Article  CAS  Google Scholar 

  88. Lin XJ, Fang JH, Yang XJ, Zhang C, Yuan Y, Zheng L, Zhuang SM. Hepatocellular carcinoma cell-secreted exosomal microRNA-210 promotes angiogenesis in vitro and in vivo. Mol Ther Nucleic Acids. 2018;11:243–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Li B, Hong J, Hong M, Wang Y, Yu T, Zang S, Wu Q. piRNA-823 delivered by multiple myeloma-derived extracellular vesicles promoted tumorigenesis through re-educating endothelial cells in the tumor environment. Oncogene. 2019;38:5227–38.

    Article  CAS  PubMed  Google Scholar 

  90. Bao L, You B, Shi S, Shan Y, Zhang Q, Yue H, Zhang J, Zhang W, Shi Y, Liu Y, et al. Metastasis-associated miR-23a from nasopharyngeal carcinoma-derived exosomes mediates angiogenesis by repressing a novel target gene TSGA10. Oncogene. 2018;37:2873–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Conigliaro A, Costa V, Lo Dico A, Saieva L, Buccheri S, Dieli F, Manno M, Raccosta S, Mancone C, Tripodi M, et al. CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer. 2015;14:155.

    Article  PubMed  PubMed Central  Google Scholar 

  92. He M, Qin H, Poon TC, Sze SC, Ding X, Co NN, Ngai SM, Chan TF, Wong N. Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs. Carcinogenesis. 2015;36:1008–18.

    Article  CAS  PubMed  Google Scholar 

  93. Mao L, Li J, Chen WX, Cai YQ, Yu DD, Zhong SL, Zhao JH, Zhou JW, Tang JH. Exosomes decrease sensitivity of breast cancer cells to adriamycin by delivering microRNAs. Tumour Biol. 2016;37:5247–56.

    Article  CAS  PubMed  Google Scholar 

  94. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Jiang K, Dong C, Yin Z, Li R, Mao J, Wang C, Zhang J, Gao Z, Liang R, Wang Q, Wang L. Exosome-derived ENO1 regulates integrin α6β4 expression and promotes hepatocellular carcinoma growth and metastasis. Cell Death Dis. 2020;11(11):972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Li T, Wan Y, Su Z, Li J, Han M, Zhou C. Mesenchymal stem cell-derived exosomal microRNA-3940-5p inhibits colorectal cancer metastasis by targeting integrin α6. Dig Dis Sci. 2021;66(6):1916–27.

    Article  CAS  PubMed  Google Scholar 

  97. Grigoryeva ES, Savelieva OE, Popova NO, Cherdyntseva NV, Perelmuter VM. Do tumor exosome integrins alone determine organotropic metastasis? Mol Biol Rep. 2020;47(10):8145–57.

    Article  CAS  PubMed  Google Scholar 

  98. Li K, Chen Y, Li A, Tan C, Liu X. Exosomes play roles in sequential processes of tumor metastasis. Int J Cancer. 2019;144(7):1486–95.

    Article  CAS  PubMed  Google Scholar 

  99. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M, Ashby J, Chow A, O’Connor ST, Li S, Chin AR, et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol. 2015;17(2):183–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, Boireau W, Rouleau A, Simon B, Lanneau D, et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest. 2010;120(2):457–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Ning Y, Shen K, Wu Q, Sun X, Bai Y, Xie Y, Pan J, Qi C. Tumor exosomes block dendritic cells maturation to decrease the T cell immune response. Immunol Lett. 2018;199:36–43.

    Article  CAS  PubMed  Google Scholar 

  103. Chennakrishnaiah S, Meehan B, D’Asti E, Montermini L, Lee TH, Karatzas N, Buchanan M, Tawil N, Choi D, Divangahi M, et al. Leukocytes as a reservoir of circulating oncogenic DNA and regulatory targets of tumor-derived extracellular vesicles. J Thromb Haemost. 2018;16(9):1800–13.

    Article  CAS  PubMed  Google Scholar 

  104. Subramanian A, Gupta V, Sarkar S, Maity G, Banerjee S, Ghosh A, Harris L, Christenson LK, Hung W, Bansal A, et al. Exosomes in carcinogenesis: molecular palkis carry signals for the regulation of cancer progression and metastasis. J Cell Commun Signal. 2016;10(3):241–9.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Lugini L, Cecchetti S, Huber V, Luciani F, Macchia G, Spadaro F, Paris L, Abalsamo L, Colone M, Molinari A, et al. Immune surveillance properties of human NK cell-derived exosomes. J Immunol. 2012;189(6):2833–42.

    Article  CAS  PubMed  Google Scholar 

  106. Hong CS, Sharma P, Yerneni SS, Simms P, Jackson EK, Whiteside TL, Boyiadzis M. Circulating exosomes carrying an immunosuppressive cargo interfere with cellular immunotherapy in acute myeloid leukemia. Sci Rep. 2017;7(1):14684.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Zhu L, Kalimuthu S, Gangadaran P, Oh JM, Lee HW, Baek SH, Jeong SY, Lee SW, Lee J, Ahn BC. Exosomes derived from natural killer cells exert therapeutic effect in melanoma. Theranostics. 2017;7(10):2732–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kibria G, Ramos EK, Wan Y, Gius DR, Liu H. Exosomes as a drug delivery system in cancer therapy: potential and challenges. Mol Pharm. 2018;15(9):3625–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gardell JL, Parker DC. CD40L is transferred to antigen-presenting B cells during delivery of T-cell fhelp. Eur J Immunol. 2017;47(1):41–50.

    Article  CAS  PubMed  Google Scholar 

  110. Muntasell A, Berger AC, Roche PA. T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. EMBO J. 2007;26(19):4263–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Xie Y, Zhang H, Li W, Deng Y, Munegowda MA, Chibbar R, Qureshi M, Xiang J. Dendritic cells recruit T cell exosomes via exosomal LFA-1 leading to inhibition of CD8+ CTL responses through downregulation of peptide/MHC class I and Fas ligand-mediated cytotoxicity. J Immunol. 2010;185(9):5268–78.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81901434, No. 81970466), China Postal Science Foundation (No. 2018M641743, No. 2019M661168) and Natural Science Foundation of Liaoning Province (No. 2019-ZD-0784).

Author information

Authors and Affiliations

  1. Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China

    Bo Wu

  2. Department of Radiology, The Fifth Hospital of Xiamen, Xiamen, 361101, China

    Qian Wang

  3. Department of Thoracic Surgery, Cancer Hospital of Liaoning Province, China Medical University, Shenyang, 110032, China

    Xiang Shi

  4. Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China

    Meixi Jiang

Authors
  1. Bo Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiang Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meixi Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BW and QW offered direction and guidance of the manuscript. BW and XS drafted the initial manuscript. QW and MX-J revised the manuscript. BW and MX-J illustrated the figures for the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Meixi Jiang.

Ethics declarations

Consent for publication

All authors agree to submit the article for publication.

Competing interests

This manuscript has been read and approved by all authors and all declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, B., Wang, Q., Shi, X. et al. Targeting Endocytosis  and Cell Communications  in the Tumor Immune Microenvironment. Cell Commun Signal 20, 161 (2022). https://doi.org/10.1186/s12964-022-00968-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12964-022-00968-3

Keywords

Cell Communication and Signaling

ISSN: 1478-811X