<p>High mobility group box protein 1 (HMGB1) is a ubiquitous protein that has multiple functions in the nucleus and cytosol. Following release into the extracellular space, HMGB1 acts as a mediator of inflammation. HMGB1 is overexpressed in many cancers and has both oncogenic and antitumoral effects. Here we investigated the role of HMGB1 expression by cancer cells in the antitumor immune response. Subcutaneous tumors were induced in mice by injection of wild-type or HMGB1-low engineered syngeneic cancer cells. Tumor growth and immune infiltration were assessed, and gene expression was analysed in whole tumors and isolated tumor cells by RNA sequencing analysis. Downregulation of cancer cell-intrinsic HMGB1 prevented tumor growth and reprogrammed the tumor microenvironment into a more inflamed phenotype. Tumor growth was not impacted in immunodeficient mice or in mice deficient in CD8⁺ T cells, demonstrating that the impact of HMGB1 downregulation on tumor progression was immune-dependent and mediated by CD8⁺ T cells. Transcriptional profiling showed that HMGB1^low tumors were enriched in immune pathways such as antigen presentation, T-cell receptor and cytokine signalling. Immune activation was robust and detectable in both tumor tissue and secondary lymphoid organs of mice bearing HMGB1^low tumors, but this did not facilitate immune infiltration of wild-type tumors that had been co-injected in the contralateral flank. We propose that tumor cell-intrinsic HMGB1 plays a critical role in modulating the local tumor microenvironment and in limiting anticancer immune responses. Thus, targeting cancer cell-intrinsic HMGB1 may represent a novel approach to improve the outcome of cancer immunotherapy.</p>