Modulation of Tumor Microenvironment by Targeting HIF-1α, Enhances the Therapeutic Efficacy of Chemoimmunotherapy in Mice Model of Colon Cancer

Abstract

purpose Recently, combination therapies have become a promising approach with hopeful therapeutic outcomes due to their strong antitumor effects. Among them, despite the great success of cancer chemoimmunotherapy, it has not been able to improve the outcome of patients. Immunosuppressive tumor microenvironment (TME) has been known as the main barrier to therapy. It has been assumed that targeting HIF-1α as a reshaping of TME combined with chemoimmunotherapy can capably enhance the antitumor response of therapy. Methods We established CT26 mouse models to assess the synergistic effect of genetic silencing of HIF-1α combined with oxaliplatin (OXA) and imiquimod (IMQ) on tumor growth and TME. Results We showed that cotreatment of HIF-1α siRNA with OXA + IMQ exhibited a significant delay in tumor growth, which was correlated with high levels of cellular immune-related cytokines. Besides, mice without HIF-1α siRNA treatment exhibited high tumor growth and high levels of immunosuppressive factors, indicating an immunosuppressive phenotype. Briefly, we found that HIF-1α inhibition could synergize with OXA and IMQ to inhibit tumor growth in vivo. Conclusions Our data suggest that targeting HIF-1α represents a promising option to augment the antitumor response of chemoimmunotherapy.