CircCLMP Suppresses Anti-Tumor Immunity by Inhibiting Activation of IRF3 and Interferon Response in Microsatellite Instability-high Endometrial Cancer

Immune checkpoint inhibitors have been proven effective for recurrent or metastatic cases of microsatellite instability-high (MSI) endometrial cancer (EC). However, drug resistance exists in a noticeable proportion of patients. Elucidating the underlying mechanisms would help develop new therapeutic strategies and benefit in improving patients' prognosis. Circular RNAs (circRNAs) are excellent biomarkers due to their stability and tissue specificity. Evidence has showed that circRNAs could mediate immune evasion in several types of malignancies. However, whether they regulate the immune response in MSI EC has not been explored. Here, based on the results of our former circRNA array, which identified the differentially-expressed circRNAs in MSI EC, we found that a circRNA, circCLMP, was negatively correlated with CD8⁺ T cell infiltration in MSI EC, and up-regulated in ICI-resistant MSI EC. <i>In vivo</i> assays showed that circCLMP could alter the anti-tumor immunity and promote tumor growth. Mechanistically, circCLMP shielded IRF3 from binding to TBK1, interfered with the phosphorylation and nuclear translocation of IRF3, thereby inhibiting the activation of interferon response, suppressing CD8⁺ T cell infiltration in the tumor environment, and eventually mediating immune evasion and promoting the progression of MSI tumors. Targeted knockdown of circCLMP combined with anti-PD-1 inhibitor treatment effectively enhanced the anti-tumor effects in the preclinical MSI EC PDX model. For the first time, our study reported an immunoregulating circRNA in MSI EC, which may provide insights into developing new biomarkers and therapeutic targets for overcoming immunotherapy resistance in MSI EC.