Cytotherapy is a revolutionary therapeutic agent representing the forefront of current cancer therapy, but its poor efficacy in the treatment of solid tumours remains challenging. Integration of tumour infiltration, targeted elimination and tumour microenvironment (TME) regulation functions in designing effective cytopharmaceuticals for solid tumours is necessary. Here, we designed on-demand editing macrophages (RILO-M1-G) constructed by surface glypican-3 (GPC3) peptide anchoring and inner R848/INCB024360-lipid particle (RILO) packing to combat hepatocellular carcinoma (HCC). Based on the tumour tendency and deep penetration of macrophages, the anchored GPC3 peptide on the membrane surface promoted macrophage-tumour cell recognition, thus enhancing specific tumour targeting and phagocytosis of tumour cells with high GPC3 expression. The packed RILOs were wrapped by C16-ceramide fused Escherichia coli-originated outer membrane vesicles (OMVs). OMVs facilitated RILO internalization through caveolin-mediated endocytosis to maintain a suitable nanostructure, C16-ceramide induced membrane invagination and exosome generation, leading to the release of packed RILOs through exosomes. These exosomes containing the TLR7/8 agonist R848 and IDO1 inhibitor INCB024360 enabled remodelling of the immunosuppressive TME by regulating the tumour-associated macrophage phenotype and enhancing T-cell viability. Furthermore, treatments with RILO-M1-G exerted remarkable therapeutic efficacy in a H22 tumour-bearing mouse model, rechallenged tumour model and orthotopic HCC mouse model compared with that of first-line HCC therapy. Overall, RILO-M1-G offered a new cytotherapeutic strategy for meeting the clinical demands of solid tumour treatment.