Beta-adrenergic receptor blocker propranolol triggers anti-tumor immunity and enhances irinotecan therapy in mice colorectal cancer

Colorectal cancer (CRC) stands as the second leading cause of cancer-related deaths worldwide with limited available medicines. While drug repurposing comes as a promising strategy for cancer treatment, we discovered that propranolol (Prop), a non-selective β1 and β2 adrenergic receptor blocker, significantly inhibited the development of subcutaneous CT26 CRC and AOM/DSS-induced CRC models. The RNA-seq analysis highlighted the activated immune pathways after Prop treatment, with KEGG analysis enriched in T-cell differentiation. Routine analyses of blood revealed a decrease in neutrophil to lymphocyte ratio, a biomarker of systemic inflammation, and a prognostic indicator in the Prop-treated groups in both CRC models. Analysis of the tumor-infiltrating immune cells exhibited that Prop regressed the exhaustion of CD4+ and CD8+ T cells in the CT26-derived graft models, which was further corroborated in the AOM/DSS-induced models. Furthermore, bioinformatic analysis fitted well with the experimental data, showing that β2 adrenergic receptor (ADRB2) was positively correlated with T-cell exhaustion signature in various tumors. The in vitro experiment showed no direct effect of Prop on CT26 cell viability, while T cells were activated with significantly-upregulated production of IFN-γ and Granzyme B. Consistently, Prop was unable to restrain CT26 tumor growth in nude mice. At last, the combination of Prop and the chemotherapeutic drug Irinotecan acted out the strongest inhibition in CT26 tumor progress. Collectively, we repurpose Prop as a promising and economical therapeutic drug for CRC treatment and highlight T-cell as its target.