Cancer-derived exosomal circTMEM56 sensitize HCC radiotherapy by augment cGAS-STING pathway in dendritic cells

Abstract Background： Dysregulation of circRNAs in cancer cells can deregulate host immune surveillance, however, their roles and mechanisms of radiotherapy (RT)-induced immune effects remain elusive. Method： By comparing tissues and serum from patients with and without abscopal effect (AE) after RT, we reported hsa_circ_0005720 (circTMEM56) was elevated in patients with AE, and circTMEM56 level related to the survival and recurrence of HCC patients. Using cells and mice with cGAS or Sting deficiency, we demonstrated that exosomal circTMEM56 level was positively associated with response to RT and promoted dendritic cell (DC) proliferation and augmented type I interferons (IFN-I) secretion. Results: Mechanistically, circTMEM56 bolstered the cGAS/STING induced type I IFN signaling to partake in the RT-resetting the tumor microenvironment through a miR-136-5p/STING axis. Importantly, the administer of exosomal circTMEM56 ameliorated the SBRT response in mice with low level of circTMEM56, and patients with low circTMEM56 are poorly responsive to RT plus anti-PD1 therapy (Clinical trials NCT03857815 and ChiCTR2200057338). Thus, we not only mechanistically elucidated a molecular axis by which circTMEM56 intensified the RT-reset tumor microenvironment, but also offered a novel effective reinforcing adjuvant for HCC RT.