Table 1.
The role of TME in sorafenib resistance of HCC.
| Research area | Molecules/Drugs/cells | Major effects | Pathway | Resources | References |
|---|---|---|---|---|---|
| Hypoxia | HIF-1α | the reduction of VEGF expression and tumor angiogenesis in HCC | HIF-1α/VEGF | in-vitro | (8, 9) |
| NF-κB | EF24 overrides sorafenib resistance through VHL-dependent HIF-1α degradation and NF-κB inactivation. | – | in-vitro and in-vivo | (10) | |
| HIF-1α and HIF-2α | indispensable for HCC cells developing sorafenib resistance and re-acquiring angiogenesis and proliferation | – | in-vitro and in-vivo | (11, 12) | |
| Sorafenib | activating the expression of VEGF and cyclin D1 | HIF-1α- to HIF-2α-dependent pathways | observational studies in patients | (13, 14) | |
| increased HIF-2α expression induced by sorafenib leads to drug resistance | TGF-α/EGFR | in-vitro | (15) | ||
| Mir-338-3p | sensitized the HCC cells to sorafenib by targeting HIF-1α | – | in-vitro and in-vivo | (16) | |
| HIF-2α inhibitor PT-2385 | improve sorafenib efficacy | the androgen receptor and the pSTAT3/pAKT/pERK | in-vitro and in-vivo | (17) | |
| PFH@LSLP | improve sorafenib efficacy | CSF1/CSF1R | in-vivo | (18) | |
| Immune microenvironment | TAMs | induce EMT and enhance stemness features | – | in-vitro and observational studies in patients | (19, 20) |
| M2 macrophages | promote tumor growth, migration, and invasion | – | in-vitro | (21) | |
| HGF | the drug resistance of HCC | HGF/C-Met, ERK1/2/MAPK and PI3K/AKT | |||
| the neutrophils | might promote or suppress cancer cells proliferation and metastasis | – | in-vitro and observational studies in patients | (22) | |
| Sorafenib | Increase the infiltration level of TANs | – | |||
| Tumor immunosuppression caused by hypoxia was also observed with continues sorafenib treatment | – | in-vivo | (23) | ||
| CCR4+ Treg | can enhance antitumor immunity, overcome sorafenib resistance, and sensitize tumors to PD-1 checkpoint blockade. | – | In-vivo and in-vitro | (24) | |
| Exosomes | Mir-122 | significantly improved the antitumor effect of sorafenib in HCC mice models | – | in-vitro | (25) |
| Si-GRP78-modifed exosomeslncRNA-VLDLR | incubation of tumor cells with EVs containing lncRNA-VLDLR significantly reduced their sensitivity to sorafenib | – | in-vitro | (26) | |
| inhibit HCC cells proliferation and invasion, as well as elevate the sensitivity to sorafenib treatment by targeting the oncogene GRP78 | – | in-vitro and in-vivo | (27) |