Table 4.

Proposed combination therapies from multi-omics studies

Proposed therapy	Analysis tools involved	Key findings	References
Anti-Tigit + anti-PD-1	CyTOF, Immunohistochemistry (IHC)/ Immunofluorescence and flow cytometry	• Combination of anti-TIGIT plus anti-PD1 reduced tumor burden and prolonged survival in HCC model • Combination therapy increased the ratio of cytotoxic CD8 T cells to regulatory T cells in tumor	Chiu et al. Gastroenterology, 2020 [145]
Anti-TNFR2 + anti-PD-1	CyTOF, scRNA seq, multiplex Immunofluorescence and flow cytometry	• TNFR2 is specific biomarker related to response to anti-PD-1 ICI • Anti-TNFR2 + anti-PD-1 provides uncoupled effect with enhanced response without the increase in irAEs	Chuah et al. J Hepatol, 2022 [93]
Metformin + anti-PD-1	Intravital imaging, transcriptomic analysis and flow cytometry	• NASH-dependent impairment of hepatic CD8+ T-cell metabolism leading to impaired response to anti-PD-1 in mice with NASH-HCC • The use of Metformin could reverse such impairment and improve the response to anti-PD-1 therapy	Wabitsch et al. J Hepatol 2022 [105]
AZD5069 (CXCR2 small molecule inhibitor) + anti-PD1	Imaging mass cytometry, RNA-seq and flow cytometry	• CXCR2-inhibition in NASH-HCC model reprogrammed the TME and enhances response to ICI • CXCR2 inhibition reprogrammed tumour-associated neutrophils (TANs) to a cytotoxic and anti-tumoral phenotypes • CXCR2 inhibition increases intratumoral XCR1 + dendritic cells and cytotoxic CD8+ T cell	Leslie et al. Gut, 2022 [147]
Gö6976 (PKCα inhibitor) or BLZ945 (targeting CSF1R) + anti-PD-1	CyTOF, multiplex immunofluorescence and RNA-sequencing	• Phosphorylation of ZFP64 promotes transcriptional activation of CSF1 and immunosuppressive M2 macrophage polarization • PKCα was identified as the upstream kinase for ZPF64 phosphorylation and hence by targeting PKCα (Gö6976) or CSF1 (BLZ945) in combination with anti-PD-1 therapy demonstrated enhanced anti-tumour activity	Wei et al. J Hepatol 2022 [146]
Cabozantinib (multikinase inhibitor) + anti-PD-1	Flow cytometry, IHC, transcriptome and cytokine profiling as well as multiplex immunofluorescence	• Esteban-Fabro et al. reported a neutrophils-medicated anti-tumour immune response enhanced by the combination of cabozantinib and anti-PD-1 • Ou et al. reported the main anti-tumour effect of the combination via the suppression of MDSCs	Esteban-Fabro et al. Clin Cancer Res 2022 [153]. Ou et al. Ann Oncol 2022 [155]