Loss of MicroRNA-29b promotes DNMT3b-mediated STING downregulation to attenuate radiotherapy-induced antitumor immunity in KRAS-mutated colorectal cancer.

The response to neoadjuvant chemoradiotherapy (neoCRT) in patients with locally advanced colorectal cancer is variable. However, the detailed mechanisms underlying the poor response to neoCRT are elusive. Here, we found that the KRAS mutation significantly influences the therapeutic response to neoCRT and tumor lapses through evasion of immune surveillance. We found that oncogenic KRAS activation led to the upregulation of DNMT3b expression, which suppressed STING expression and attenuated radiotherapy (RT)-induced antitumor immunity. Oncogenic KRAS activation significantly decreased miR-29b-3p expression, resulting in DNMT3b upregulation, which in turn decreased RT-induced STING signaling for type I interferon (IFN) production. We found that supplementation with colorectal cancer-specific miR-29b-3p markedly increased the response to radiotherapy in KRAS-mutated CRC tumors in vivo and significantly reshaped the tumor microenvironment to promote immune cell infiltration. Furthermore, supplementation with miR-29b-3p also enhanced the response to immune checkpoint blockade as well as radiotherapy. Taken together, these results suggest a therapeutic approach in which tumor-specific miR-29b-3p increases the benefits of RT by overcoming defective STING in KRAS-mutated CRC patients.