Table 1.

BCLM therapeutic targets

Section	Target	Study	Research subjects	Reference
Immune microenvironment	CXCR4	an open label, phase Ib/II trial to study the safety, tolerability and anti-tumor activity of X4P-001 in combination with toripalimab in patients with locally advanced or metastatic TNBC	human	NCT05103917
		a phase 1 study to evaluate the pharmacokinetics and safety of MB1707 in patients with advanced cancer	human	NCT05465590
		aHSC-secreted chemokine CXCL12 induces NK cell quiescence through its cognate receptor CXCR4 to suppress NK cell-sustained breast cancer dormancy	mice	Correia et al.8
	CXCR3	IP-10 (CXCL10) can trigger emergence of dormant breast cancer cells in a metastatic liver microenvironment	ex vivo hepatic MPS	Clark et al.9
	PD-L1	seed- and soil-dependent differences in murine breast tumor microenvironments dictate anti-PD-L1 IgG delivery and therapeutic efficacy	mice	Liu et al.10
	CTLA-4	phase I/II randomized study of NBTXR3 activated by Abscopal or RadScopal radiation in combination with immunotherapy (anti-CTLA-4 and anti-PD-1) for patients with advanced solid malignancies	human	NCT05039632
	CD47	a phase 1, open-label, multicenter, dose escalation study evaluating the safety, tolerability, and preliminary efficacy of IMM2902 in patients with HER2-expressing advanced solid tumors	human	NCT05076591
	CCDC25	DNA of neutrophil extracellular traps promotes breast cancer metastasis to liver	mice	Yang et al.11
	a-UPR	ErSO, a small-molecule activator of the unfolded protein response eradicates human breast tumors in mice	mice	Boudreau et al.12
	STAT3	combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways inhibits breast cancer metastasis to the liver and lung	mice	Doheny et al.13
		simultaneous inhibition of breast cancer and its liver and lung metastasis by blocking inflammatory feedforward loops	mice	Lu et al.14
	GATM/MPS1	creatine promotes breast cancer metastasis to the liver by activating Smad2/3	mice	Zhang et al.15
	IL-6	nobiletin inhibits breast cancer liver metastasis by suppressing the IL-6-induced ERK-STAT and JNK-c-JUN pathways	mice	Wu et al.16
Metabolic reprogramming	Myc	phase 1/2 open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of OTX-2002 as a single agent and in combination with standard of care in patients with hepatocellular carcinoma and other solid tumor types known for association with the MYC oncogene	human	NCT05497453
	PI3K	SOX2-OT induced by PAI-1 promotes TNBC cells metastasis to liver and lung by sponging miR-942-5p and activating PI3K/Akt signaling	Mice	Zhang et al.17
	PKM2	circular RNA KIF4A promotes liver metastasis of breast cancer by reprogramming glucose metabolism	Mice	Huang et al.18
	AKT	dietary alterations modulate the microRNA 29/30 and IGF-1/AKT signaling axis in breast cancer liver metastasis	Mice	Shastri et al.19
Extracellular vesicles	MMP	microenvironment-induced TIMP2 loss by cancer-secreted exosomal miR-4443 promotes liver metastasis of breast cancer	Mice	Wang et al.20
Tumor vascular	EGF	phase I trial of cetuximab and erlotinib (EGFR inhibitors) and SIR-Spheres (yttrium microspheres) in patients with advanced malignancies and liver metastases	human	NCT01432119
EMT	TGF-β	fresolimumab and radiotherapy in metastatic breast cancer	human	NCT01401062
	CXCR4	the FUS/circEZH2/KLF5/feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing EMT	Mice	Liu et al.21
	cytoskeleton-associated proteins	lovastatin inhibits EMT and metastasis of TNBC stem cells through dysregulation of cytoskeleton-associated proteins	mice	Zheng et al.22
Others	circROBO1	circROBO1 facilitates the carcinogenesis and liver metastasis of BC through the circROBO1/KLF5/FUS feedback loop, which inhibits the selective autophagy of afadin by suppressing the transcription of BECN1	mice	Wang et al.23
	S100A10	S100A10 functions as a metastasis promoter of breast CSCs by conferring both invasion ability and CSC properties in breast cancers	mice	Yanagi et al.24
	Notch1	ezrin accelerates breast cancer liver metastasis through promoting furin-like convertase-mediated cleavage of Notch1	mice	Chen et al.25
	AGR3	anterior gradient 3 promotes breast cancer metastasis to liver and bone and chemotherapy response	human	Xu et al.26
	ER	estrone, the major postmenopausal estrogen, binds ERa to induce SNAI2, epithelial-to-mesenchymal transition, and ER+ breast cancer metastasis	mice	Qureshi et al.27

CXCR4, C-X-C chemokine receptor type 4; TNBC, triple-negative breast cancer; aHSC, activated hepatic stellate cells; CXCL12, C-X-C motif chemokine ligand 12; NK, natural killer; CXCR3, C-X-C motif chemokine receptor 3; CXCL10, C-X-C motif chemokine ligand 10; MPS, microphysiological systems; PD-L1, programmed cell death-ligand 1; IgG, immunoglobulin G; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; CD47, cluster of differentiation 47; HER2, human epidermal growth factor receptor 2; CCDC25, coiled-coil domain containing 25; DNA, deoxyribonucleic acid; UPR, unfolded protein response; STAT3, signal transducer and activator of transcription 3; JAK2, Janus kinase 2; SMO, smoothened; GLI1, GLI family zinc finger 1; GATM, glycine amidinotransferase; MPS1, mucopolysaccharidosis 1; IL-6, interleukin-6; ERK, extracellular regulating kinase; JNK, Jun N-terminal kinase; PI3K, phosphatidylinositide 3-kinase; SOX2-OT, SOX2 overlapping transcript; PAI-1, plasminogen activator inhibitor-1; PKM2, pyruvate kinase isozyme type M2; IGF-1, insulin-like growth factors 1; MMP, matrix metalloproteinase; TIMP2, TIMP metallopeptidase inhibitor 2; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; TGF-β, transforming growth factor β; FUS, fused in sarcoma/translocated in liposarcoma; KLF5, KLF transcription factor 5; CSC, cancer stem cell; AGR3, anterior gradient 3; ER, estrogen receptor; SNAI2, snail family transcriptional repressor 2.