Synergistic Effects of HIF-1α Inhibition, Toll-Like Receptor 7 Agonist, and Chemotherapy in Mice Model of Colon Cancer

Abstract

Recently, combination therapies have become a promising option 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 recognized as the main barrier to immunotherapy. So, it has been assumed that targeting HIF-1α as a reshaping of TME combined with chemoimmunotherapy can capably enhance the antitumor response of therapy. Herein, we have studied the therapeutic effects of HIF-1α inhibition combined with chemoimmunotherapy. 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. We showed that in comparison with dual combination therapy, mice treated with triple combination therapy 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. Our data suggest that targeting HIF-1α represents a promising strategy to enhance the antitumor response of chemoimmunotherapy.