Table 1.

Molecules upregulated in acidic and hypoxic Mexo. List of molecules upregulated in exosomes secreted in hypoxic (blue) and acidic (orange) TME. Targets and functional effects on tumour progression are described in several tumour types as reported in References. N.D., not detected targets, * Refer to Supplementary Data S1 for the specific reference list.

Molecule	Targets	Functional Effects	Bibliography *
miR-494	BIM; PTEN	Modulates cell proliferation; promotes cell migration and invasion; enhances angiogenesis and tumour growth under hypoxic conditions.	[1,2,3]
miR-1290	SOCS4; LHX6; CCNG2; IKK1; NKD1; INPP4B	Promotes cell proliferation, tumour growth, metastatization and EMT; supresses apoptosis and increases resistance to chemo-radiation	[4,5,6,7,8,9,10]
AKR7A2	Succinic semialdehyde	Supports gamma-Hydroxybutyrate production	[11]
DDX39B	Pre-ribosomal RNA; BRCA1 mRNA	Enhances cell proliferation and increases cell chemotherapy resistance	[12,13]
EIF3C	PI3K/Akt/NF-κB; THBS1, RAP1A, CYR61, ADAMTS1, TUFT1, CFL2, EPHA and EPHB; WNT5B, DHH, SMO, RAC2, PCSK1N and INMBA	Promotes cell proliferation, survival, migration and invasiveness	[14,15,16]
	N.D.	Impairs the sensitivity to EGFR-TKI (Erlotinib) by enhancing the autophagic activity	[17]
FARSA	Activated by FARSA-AS1	Promotes tumour growth and metastasis	[18]
circFARSA	miR-330-5p/LASP1	Enhance proliferation, migration, and invasion	[19]
PMRT5	H3R8, H4R3 and RBL2; CUL4AB promoters; PDCD4; eIF4E; E2F1; HIF-1	Promotes cancer cell proliferation and inhibits apoptosis	[20,21,22,23,24,25]
	MDM4	Supports drug resistance to palbociclib	[26]
	IFI16 and NLRC5	Impairs antitumor immune response	[27]
	BCL6	Regulates the germinal centre reaction	[28]
VARS	TCTP-EF1A2	Promotes tumorigenesis and tumour progression	[29,30]
hnRNP L	miR-574-3p; AXL; SRSF3; p53, Bcl-2, caspases-3, -6, -9 and MAPK; SPRY4-IT1	Promotes cell proliferation and inhibits apoptosis, enhances tumorigenesis and the tumour metastatic potential	[31,32,33,34,35,36]
hnRNP K	MAP 1B-LC1; SRSF1; DUSP1; EZH2-SOX2; CCND1, G0S2, XAF1 and ERCC4; MMP12 and ß-catenin; XIAP; GSN mRNA; MMP-2	Promotes EMT, cell proliferation, migration and invasion; role in chemoresistance	[37,38,39,40,41,42,43,44]
	PTGS2, CCK3, RAS, ERK and MMP-3.	Promotes tumour metastasis regulating extracellular matrix, cell motility, and angiogenesis pathways	[45]
RAN	Importin-β; RhoA; Caspase-3; AR; Met and c-Met receptor; PI3 kinase; Txl-2b; AR and CXCR4; Cyclin A, Cyclin D1, Cyclin E, CDK2, CDK4, phospho-Rb and Survivin; PI3K/Akt/mTORC1 and Ras/MEK/ERK; FGF2; Aurora Kinase A; miR-21	Enhances tumorigenesis; inhibits apoptosis; promotes cell proliferation, migration and invasion; promotes gefitinib resistance	[46,47,48,49,50,51,52,53,54,55,56]
NRAS and HRAS	BRAF, PI3K, PLC/PKC, RAL	Promote proliferation, survival and cell growth, and enhances cell migration	[57]
	SDF-1, I-TAC, CCL9/10, and MCP5	Induces the tumour immune escape	[58]
HSPA1L	IGF1Rβ and β-Catenin	Enhances EMT and Cancer Stem Cell-like properties	[59]
	HIF-1α/GP78	Promotes the cellular prion protein (PrPC) accumulation and tumorigenicity	[60]
HSPA5 (GRP78)	VEGFR-2; Kringle 5	Promotes vascularization	[61,62]
	TFEB, CSTD, CTSL, and LAMP1	Supports cell protection against ER stress and ROS damage; regulates lysosomal activity	[63]
	ATF4-DDIT4-mTORC1	Induces pro-survival autophagy	[64]
	Cripto; Proteinase inhibitor α2-macroglobulin (α2M *); FAK; PRMT7; PI3K/Akt/Mdm2	Activates EMT and promotes cell proliferation, migration and invasion	[65,66,67,68,69]
	Raf-1; Caspase-7; PERK; Wnt	Inhibits apoptosis and enhances cell survival	[70,71,72,73]
	CD5L; CHOP, Bcl-2 and Bax; GPX4; ERK/AKT and BOK/NOXA	Involved in chemoresistance	[74,75,76,77]
	IL-10, TGF-β and IDO; PD-L1; LAP/TGF-beta	Supports tumour immune escape; cell protection from CTL-mediated lysis	[78,79,80]
HSP90B1 (GRP94 and GP96)	Twist1	Promotes vasculogenic mimicry	[81]
	CCT8/c-Jun; AKT and eNOS; TGF-β1; Ack1; RAC1, VAMP2, LAMP1, SYNE2, integrin α2/αL; Wnt/β-catenin	Contributes to tumorigenesis and promotes cell migration, invasion and metastasis	[82,83,84,85,86,87]
	Mdm2 E3 ligase	Inhibits apoptosis and decreases p53 levels	[88]
	Proteasome and MHC molecules	Participates in peptide generation and modulates immune system	[89]
	TGF-β and SMAD2	Induces Treg infiltration by promoting the TGF-β signalling pathway.	[90]
	TNF-α, IL-10, IL-12 p70 and IFN-γ	Promotes T cell response, enhances DC antigen presentation and induces cytokine secretion	[91]
HSP90AB1	VEGFR	Promotes endothelial tumor angiogenesis and accelerates neovascularization	[92]
	Bcl-2	Inhibits cell apoptosis and increases the caspase activation	[93]
	Fibronectin	Induces fibronectin exocytosis and formation of extracellular matrix	[94]
	ERBB2 and CDK4; LRP5	Promotes cell proliferation, invasion and migration, tolerance to chemotherapeutic drugs and in vivo metastasis	[95,96]
CFL2	miR-3189-3p; miR-369-3p; miR-1299	Enhances cell proliferation and migration; impairs tumour cell apoptosis	[97,98,99]
GSN	Nm23-H1; MCL-1, MMP-2 and MMP-9; p-AKT and p-P38	Promotes cell growth, migration and invasion and in vivo tumour growth	[100,101,102]
	XIAP, FLIP, Akt and AIF; PSME2, PTK2B, FOS, JUN, ITGB1, MAP2K7, MAP3K4, MAP3K12, Rac1 and RRM2B	Inhibits apoptosis; supports the response to cisplatin	[103,104]
TIMP3	Tnfr1	Supports early stage of tumorigenesis	[105]
GANAB	Wnt/β-catenin	Promotes proliferation and suppresses apoptosis	[106,107]
HYOU1	LDHB mRNA; IFN-type I; CHOP; VEGF; PI3K/AKT; MMP-2	Promotes proliferation, migration, invasion of cancer cells and inhibits apoptosis	[108,109,110,111,112,113]
Sphingo-mielin	KRAS	Increases the growth of oncogenic K-Ras-transformed tumours	[114]
	EGFR/ErbB1	Modulates cell motility and focal adhesion clustering	[115]