Figure 8.

Schematic of the mechanism of interaction between low‐dose sorafenib and R848 in the syngeneic mouse model of HCC. Combined treatment with low‐dose sorafenib and R848 reprograms the tumor immune microenvironment by increasing the population and activation of antitumor macrophages and neutrophils and inhibiting immunosuppressive signaling. The transition of classical M1 macrophages to FTH1^high M1 macrophages facilitates an increase in neutrophil recruitment, an increase in iron uptake, and inhibition of iron release for tumor growth tropism after combination treatment. Then, the close interaction of neutrophils/classical M1 macrophages with DCs via some ligand–receptor pairs enhances antigen presentation by DCs through MHC class I molecules, allowing enhanced tumor antigen presentation to cytotoxic CD8⁺ T cells, resulting in antitumor immunity in HCC. TNF‐α secreted by T cells contributes to vascular normalization, and the vascular‐normalized environment induced by the combination treatment in turn supports immune cell infiltration and drug perfusion, forming an antitumor positive feedback loop.