. Author manuscript; available in PMC: 2025 Aug 27.

Published in final edited form as: Semin Liver Dis. 2025 Mar 5;45(1):33–51. doi: 10.1055/a-2551-0724

Table 3:

HSC targeting strategies in liver cancer.

Therapeutic Approach	Therapeutic target	Therapy	Effect	Reference
Targeting HSCs activation and CAFs	TGF-β signaling inhibition	anti-TGFβ, (e.g. fresolimumab and metelimumab)	Reduces HSC activation and myofibroblast differentiation but failed in clinical trials	Oh, D. et al. 2024[203] Tacke, F. et al. 2023[165] Henderson, N. et al. 2020[166]
	FAP+CAF (including my CAF)	Bispecific antibodies and FAP-targeting, CAR T-cells	In preclinical models, reduce ECM, improve T-cell infiltration, control tumor growth.	Sakemura R, et al. 2022 [168] Liu Y, et al.2023[169] Das S, et al. 2023 [170] Lo A, et al. 2015 [171]
	MSLN+CAF (mes/CAF, apCAF and mesothelial cells)	MSLN-targeting CAR T-cells	Sustained antitumor effect, with a stronger antitumor response.	Zhai X, et al.2023 [177] Huang H, et al.2022 [178] Amit U, et al. 2024 [179] Schoutrop E, et al. 2021 [180]
	Dual targeting: Nectin-4, FAP, MSLN	nectin-4/FAP-CAR T-cells and MSLN-CAR T-cells	Simultaneous targeting of CAFs and tumor cells.	Li F, et al.2022 [181] Wehrli, et al. 2024[182]
	TEM1 expressing CAF	TEM1-directed CAR T-cells	CAF depletion, tumor vasculature disruption, and reduced metastasis in syngeneic models of breast tumor.	Ash SL, et al.2024 [183]
Targeting senescent HSC-derived CAFs	Senescent cells	Senolytics: Bcl2 inhibitor Navitoclax (ABT-263) or Dasatinib/Quercetin combination	Navitoclax + sorafenib phase 1 did not show clinical benefit in HCC (NCT01364051). In breast cancer and PDAC, targeting senescent CAFs can reduce immunosuppression and enhance immune infiltration.	Montori, M. et al. 2022 [147] Mertens JC, et al. 2013[125]
Targeting senescent HSC-derived CAFs	uPAR+ cells (upregulated in senescent cells)	uPAR-targeting CAR T-cells	Reduce fibrosis in MASH mouse model.	Amor, C. et al. 2020 [48]
Targeting stiffness and ECM signaling	Collagen cross-linking activity of lysyl oxidase-like 2 (LOXL2)	anti-LOXL2 antibodies (e.g. Simtuzumab)	Improve T cell migration, reduces oxidative phosphorylation and tumor growth.	Nicolas-Boluda et al. 2020 [188] Lewinska M, et al. 2024 [190]
Targeting stiffness and ECM signaling	Collagen receptor DDR1	Dasatinib (approved by the US FDA) has activity against DDR1 but not specific	Reduce tumor proliferation in preclinical model of HCC.	Filliol, A. et al. 2022[13]
Targeting CAF-secreted mediators	IL-6/IL6R	Anti-IL-6, or IL-6Rantibodies (e.g. Tocilizumab)	IL-6 neutralizing antibody blocks crosstalk between vascular CAF and tumor cells	Xu, Z. et al. 2021[204] Huang, B. et al. 2022[144] Johnson, DE. et al. 2018[145]
Targeting CAF-secreted mediators	c-MET	c-MET inhibitor (e.g. Cabozantinib)	Blocking HGF/cMet axis is expected to reduce tumor growth in iCCA, but showed limited efficacy and significant toxicity in CCA patients	Kakkar T, et al. 2007[194]