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Page 12 Asao et al. Extracell Vesicles Circ Nucleic Acids 2023;4:461-85 https://dx.doi.org/10.20517/evcna.2023.37

However, there are other metabolic effects of EVPs in cancer that are worth exploring, as well as additional
systemic effects of EVPs beyond metabolic changes. In particular, EVPs can impact amino acid metabolism,
which is crucial for cancer cell survival and proliferation, as some cancer cells have been reported to release
EVPs containing enzymes involved in amino acid metabolism. This may contribute to the reprogramming
of recipient cells and promote tumor growth . Furthermore, EVPs derived from cancer cells with
[104]
dysfunctional mitochondria transfer their mitochondrial DNA and proteins to healthy cells and influence
mitochondrial function in recipient cells [127,128] , leading to altered energy metabolism and contributing to the
development and progression of cancer.

Immune System
The interplay between cancer and the immune system has been a topic of intense research for the past four
[129]
decades . In the early 2010s, studies began to highlight the role of tumor-derived EVPs in modulating
immune responses [25,53-55,74] .

A pivotal study by Pucci et al. uncovered the role of lymph node subcapsular sinus (SCS) macrophages in
suppressing melanoma progression, by restricting tumor-derived EVP interactions with B cells .
[56]
Melanoma-derived EVPs are capable of stimulating B cells to create a pro-tumoral environment that
supports melanoma growth. However, SCS macrophages capture these tumor-derived EVPs, thereby
reducing their ability to interact with B cells and preventing the establishment of a pro-tumoral
environment . Tumor-derived EVPs carry immune-modulatory molecules, such as programmed cell
[56]
death-ligand 1 (PD-L1), and to suppress antitumor immune responses by inhibiting the function of T cells,
natural killer (NK) cells, and dendritic cells (DCs) [53,55] . Furthermore, tumor-derived EVPs stimulate Toll-
like receptor 3 (TLR3) activation in lung epithelial cells, which in turn initiate an inflammatory cascade and
promote PMN formation . These findings indicate that host lung epithelial cell TLR3 and recruited
[74]
neutrophils cooperate in reprogramming immune cells within the PMN, fostering a pro-metastatic
inflammatory microenvironment that supports lung colonization of metastasis-initiating cancer cells.
Interestingly, a study by Ortiz et al. revealed that tumor-derived EVPs selectively downregulate interferon
alpha and beta receptor subunit 1 (IFNAR1) in leukocytes, compromising the immune system's ability to
counter tumor metastasis by interfering with the protective IFNAR1-cholesterol 25-hydroxylase (CH25H)
pathway, essential for preventing tumor-derived EVP uptake and PMN formation . The IFNAR1 receptor
[54]
is significantly downregulated in leukocytes of melanoma patients with metastatic disease compared to
healthy donors or patients without metastases, rendering normal cells more vulnerable to tumor-derived
EVP uptake, leading to PMN formation. Additionally, Yin et al. explored how tumor-derived EVPs
promote the dysfunction of tumor-infiltrating dendritic cells, highlighting that lipid accumulation may
+
[130]
drive impairment in priming cytotoxic CD8 T cells . The authors demonstrated that tumor-derived
EVPs, rich in fatty acids, contributed to the observed lipid accumulation and ensuing immune dysfunction
in these bone marrow-derived dendritic cells. Notably, peroxisome proliferator-activated receptor α
(PPARα)-dependent metabolic shift in dendritic cells from glycolysis to oxidative phosphorylation
(OXPHOS), underlining the significance of PPARα-controlled fatty acid metabolism pathways, and PPARα
inhibition ameliorated lipid accumulation and improved dendritic cell immune function. Moreover, cancer-
derived EVPs can induce immune suppression by inhibiting T cell activation [55,131,132] , NK cell-mediated
cytotoxicity , and promoting the polarization of macrophages towards a tumor-promoting
[133]
phenotype [134-137] . The discovery of these immunosuppressive mechanisms has spurred the development of
combination therapies that aim to target tumor-derived EVPs in conjunction with immune checkpoint
inhibitors to enhance antitumor immunity .
[138]