Multi‐omics integration reveals the oncogenic role of eccDNAs in diffuse large B‐cell lymphoma through STING signalling

Abstract Background Extrachromosomal circular DNAs (eccDNAs), a type of double‐stranded DNAs (dsDNAs) that facilitate the activation of the DNA sensing machinery, have been implicated in the progression and prognosis of various diseases. While the roles of eccDNAs remain contentious, their significance in diffuse large B‐cell lymphoma (DLBCL) has not been reported. Methods Circular DNA sequencing (circle‐seq) was used to demonstrate the expression profile of eccDNAs in DLBCL, and atomic force microscopy to validate the presence of eccDNAs. CCK‐8 and scRNA‐seq techniques were employed to uncover the activation of eccDNA in the STING pathway, leading to enhanced cell proliferation. Chemotherapeutic drugs were used to test the hypothesis that DNA damage induces the production of eccDNA, thereby activating the STING pathway independent of cGAS. GEO databases were used for verification of the prognosis of the eccDNA‐related genes, and animal models were used to investigate the synergistic effects of DNA damage therapy in combination with STING inhibitors on anti‐tumour responses. Results EccDNAs were widely expressed in DLBCL and associated with the prognosis of patients. Elevated abundance of eccDNAs promoted the progression of DLBCL. Chemotherapeutic drugs‐induced DNA damage triggered the generation of eccDNAs, resulting in the activation of the STING signalling in a cGAS‐independent manner. Moreover, inhibition of STING exerted a synergistic anti‐tumour effect with cisplatin. Conclusions EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. This finding offers a rational therapeutic strategy combining chemotherapy with targeting STING. Highlights EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. The combined treatment of chemotherapeutic drugs with STING inhibitor significantly delayed the tumor progression, providing new insights into the therapeutic strategy for patients with DLBCL, particularly the relapsed and/or refractory (R/R) ones.