Provoking myofibroblast death: Strategies to resolve fibrosis and remodel tumor microenvironment

Table 1 Strategies inducing myofibroblast death

Target	Mechanism	Drugs/strategy developed	Disease	Ref.
YAP/TAZ-pathway	Mechano transduction	Verteporfin (YAP TEAD complex inhibitor)	Renal fibroblasts, breast cancer, pancreatic cancer	[32-34]
		CA3	Triple negative breast cancer	[38]
		Dasatinib	Prostate cancer	[39]
Lipid bilayer	Myofibroblast membrane integrity	Di-RHA	Hypertrophic scar	[42]
TGF-β receptor I	Targeting drug penetration and apoptosis by TC-therapy	TGF-β receptor I inhibitor (SB525334) and DTX-M	Pancreatic cancer model	[43]
BCL-XL	Mitochondrial priming and BCL2 mediated apoptosis	Navitoclax (ABT-263)	Lung fibrosis	[50]
MCL-1	BH3 mimetic	S63845	Breast cancer TME	[51]
FAK	Protein kinases	Antibody drug conjugate (IN10018)	Breast and gastric cancer CAFs	[53]
		siRNA based	Bleomycin-induced lung fibrosis	[54]
Rho kinase actin	Cytoskeletal dynamics	ROCK inhibitor (Y-27632)	Bleomycin-induced lung fibrosis	[58]
		Fasudil (a small-molecule ROCK inhibitor)	Lung fibrosis	[59]
Mitochondrial mediated intrinsic apoptotic pathway	ROS	Lycorine	HS in rabbit ear model	[69]
Copper ionophore		Elesclomol	Hypertrophic scars	[71]
TDO2-positive myofibroblasts	Immune privilege	LM10	OSF	[77]
FAP	CAR-T therapies	Anti-FAP-F19-ΔCD28/CD3ζ	Mesothelioma cells	[84]
Nectin4 and FAP		Nectin4-7.19 CAR-T cells	Nectin4-positive advanced solid tumours	[88]
FAP		Claudin 18.2-specific CAR-T cells	PDAC	[89]
FAP		FAP-CAR T cells	Cardiac fibrosis	[90]
FOXO4-p53 interaction	Senolytics	FOXO4-DRI peptide	Keloid fibrosis	[92]
Senescence markers like CDKN2A and SA-β-gal		Dasatinib and quercetin	Idiopathic lung fibrosis	[93]
HSP90		17-DMAG	Murine embryonic fibroblasts to study aging	[94]

YAP: Yes-associated protein; TAZ: Transcriptional coactivator with PDZ-binding motif; TEAD: TEA domain transcription facto; CA3: Carbonic anhydrase 3; TC: Two-stage combination; RHA: Rhamnolipid; TNF-α: Tumor necrosis factor α; DTX-M: Docetaxel loaded micelles; BCL-XL: B-cell lymphoma 2-long isoform; MCL-1: Myeloid cell leukaemia-1; BH3: B-cell lymphoma 2 homology 3; TME: Tumor microenvironment; FAK: Focal adhesion kinase; siRNA: Small interfering RNA; CAFs: Cancer-associated myofibroblasts; ROCK: Rho-associated coiled-coil containing protein kinase; HS: Hypertrophic scars; TDO2: Tryptophan 2,3-dioxygenase; OSF: Oral submucous fibrosis; FAP: Fibroblast activation protein; ROS: Reactive oxygen species; CAR-T: Chimeric antigen receptor T; PDAC: Pancreatic ductal adenocarcinoma; FOXO4: Forkhead box O4; CDKN2A: Cyclin dependent kinase inhibitor 2A; SA-β-gal: Senescence-associated β-galactosidase; HSP90: Heat shock protein 90; 17-DMAG: 17-Dimethylaminoethylamino-17-demethoxygeldanamycin.