Cancer associated fibroblasts in cancer development and therapy

Jia, Hongyuan; Chen, Xingmin; Zhang, Linling; Chen, Meihua

doi:10.1186/s13045-025-01688-0

Journal of Hematology & Oncology

Table 3 Strategies to targete CAFs for cancer therapy

From: Cancer associated fibroblasts in cancer development and therapy

Target	Drugs	Class	Strategy	Mechanism	Cancer models	Refs
FAP	αFAP-Z@FRT, nano-PIT, scFv-Z@FRT, mAb-IR700	FAP-specific single chain variable fragment (scFv)-conjugated photosensitizer	Depletion of CAFs	Targeting FAP + CAFs by photodynamic therapy, eliciting cellular immunity against FAP + CAFs and tumor cells	Breast cancer, ESSC	[234,235,236,237]
FAP	αFAP-PE38	FAP-targeting immunotoxin	depletion of FAP + CAFs	Depletion of FAP + CAFs, modulating TIME	Breast cancer	[229]
FAP	PT630	FAP and DPPIV inhibitor	Targeting ECM	FAP activity inhibition	Lung and colon cancers	[77]
FAP	CAP-NPs	Drug-loaded FAP cleavable nanoparticles	Targeting ECM	FAP mediated drug release	Prostate cancer	[230]
FAP	FAPα-Vax	FAP expressing tumor cell vaccine	Depletion of CAFs	Reverse immunosuppressive TME by depletion FAP + CAFs	Breast cancer, CRC	[174, 228]
PDGFR pathway	Imatinib	PDGFR inhibitor	Blocking cross-talk of CAFs and TME	Reducing growth factors and angiogenic factors secreted by CAF	Cervical cancer	[123]
CTGF	FG-3019	anti-CTGF	Blocking cross-talk of CAFs and TME	Enhancing chemotherapy response by downregulation of the X-linked inhibitor of apoptosis protein	PDAC	[81]
Hedgehog pathway	IPI-926	smoothened	Targeting ECM	Enhancing tumor vasculature and perfusion to faciliate drug deliveryinhibition	PDAC	[196]
Sst1 somatostatin receptor	Pasireotide	somatostatin analogue	CAFs normalization	Activating the sst1 receptor on CAFs and reducing synthesis of secreted proteins including IL‐6	PDAC	[220]
CXCL12-CXCR4 axis	AMD3100	CXCR4 inhibitor	Blocking cross-talk of CAFs and TME	Blocking the SDF1–CXCR4 ineraction to increase CD8 + T cell infiltration	PDAC	[87]
Vitamin A metabolism	ATRA	Vitamin A analogue	CAFs normalization	Inducing quiescence of PSCs and reducing cancer cell proliferation by recovery of Vitamin A storageand PSC deactivation	PDAC	[243, 245]
Vitamin D receptor	Calcipotriol	vitamin D analogue	CAFs normalization	reprogramming PSCs to the quiescent state and reducing ECM depostionactivation and PSC deactivation	PDAC	[249]
Angiotensin receptor	Losartan-loaded C16-N	peptide hydrogel as a local losartan depot	CAFs normalization	normalizing CAFs through down-regulation of thrombospondin-1, inhibiting TGFβ pathway	Breast cancer	[185]
TGF-β	LY2157299, LY2109761	Inhibitor of TGF-β receptor I	CAFs normalization	Blocks the fibroblast activation induced byTGF-β	Ovary cancer,HCC	[209, 213]
TGF-β	Artesunate (ARS) and dihydroartemisinin (DHA)	Artemisinin derivatives	CAFs normalization	Inactivates CAF and inhibits metastasis	Breast	[172]
TGF-β	Pirfenidone	TGF-β antagonist	CAFs normalization	inhibiting CAF proliferation by induction of apoptosis	Breast	[195]
NAD(P)H Oxidase-4 (NOX4)	GKT137831	NOX4 inhibitor	CAFs normalization	Reverts the myofibroblastic-CAF phenotype and delays tumor growth	Head and neck cancer, colorectal cancer, esophageal adenocarcinoma	[241]
CSF1R + CXCR2	JNJ-40346527 and SB225002	CSF1R inhibitor and CXCR2 inhibitor	Blocking cross-talk of CAFs and TME	Blocks pro-tumoral PMN-MDSC recruitment and reduces tumor growth	Lung, breast, colon, others	[114]
sTRAIL	sTRAIL LPD	plasmids encoding sTRAIL loaded lipid-coated protamine DNA complexes	CAFs normalization	Reverses CAFs to a quiescent state and triggers tumor cell apoptosis	Bladder carcinoma	[242]
integrin αvβ3	ProAgio	Protein targeting integrin αvβ3	Depletion of CAFs	Reduces intratumoral collagen and decreases growth factors released from CAFs by inducing apoptosis in integrin αvβ3–expressing CAFs	TNBC	[225]
Nuclear receptors (NRs)-retinoic acid receptor β and androgen receptor	EB1089 and LE135	Retinoic acid receptor β and androgen receptor antagonists	CAFs normalization	inhibits the pro-cancerous functions of CAFs and reducing chemoresistance	skin SSC	[139]
GPR77	Anti-GPR77 antibody	mAb	Depletion of CAFs	Depletion of GPR77 + CAFs to reverse resistence to chemotherapy and stemness	Breast cancer	[153]
CCR2	sc-202525	CCR2 inhibitor	Blocking cross-talk of CAFs and TME	Reversing recruitment of monocytes and their transformation to MDSCs	Lung cancer	[110]
IL-6	tocilizumab	Anti-IL-6 receptor monoclonal antibody	Blocking cross-talk of CAFs and TME	Reverses inhibition of chemotherapy-induced apoptosis by blocking CAFs derived IL-6	Gastric cancer	[215]
IGF2/IGF1R axis	linsitinib	small molecular inhibitor	Blocking cross-talk of CAFs and TME	Blocking IGFR2 mediated interaction between CAFs and T cells via CXCL12 and PD-L1	Breast cancer, CRC, melanoma	[89]
NAMPT	NAMPT-containing Evs	culture supernatant of mouse BMDM overexpressing Nampt	Blocking cross-talk of CAFs and TME	EVs containing NAMPT restore CD8 + T cell function by inhibiting NNMT expression in CAFs	gastric cancer	[222]
Senescent CAFs	ABT-199(venetoclax)	BCL-2 inhibitor	Depletion of CAFs	Depletion of senescent CAFs to restore CD8 + T cell activity		[238]
IL-34	anti-IL-34	mAb	Blocking cross-talk of CAFs and TME	Inhibiting M2 polarization mediated by AKAP12 + CAFs derived IL-34	breast cancer	[221]

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