Many cancer patients don’t benefit from currently-approved immune checkpoint inhibitors (ICI), suggesting that additional immunomodulation of the immunosuppressive tumour microenvironment (TME) is required. MTL-CEBPA specifically upregulates expression of master myeloid transcription factor, CEBPA, relieving myeloid-driven immunosuppression. Here, we report the safety, tolerability, pharmacokinetics, and efficacy of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumours that typically show ICI resistance. Multimodal exploratory analyses of paired patient biopsies demonstrate biological changes associated with combination treatment of MTL-CEBPA and pembrolizumab, including increased infiltration of T cell and antigen-presenting cells supporting conversion from an immune desert towards a more immune-inflamed TME. Patients with disease stabilisation demonstrate reductions in immunosuppressive myeloid cells post-treatment. Collectively, these data support a role for MTL-CEBPA in reducing immunosuppression in the TME. This study was registered at ClinicalTrials.gov (NCT04105335). This manuscript also reports proteomic data from patients treated with MTL-CEBPA in combination with sorafenib from clinical trial, OUTREACH, accessible at ClinicalTrials.gov, number NCT02716012 and reported. Stored plasma from patients from this clinical trial were analysed using OLINK as described below.