Targeting RNA Exonuclease XRN1 Potentiates Efficacy of Cancer Immunotherapy

Despite the remarkable clinical responses achieved with immune checkpoint blockade therapy, the response rate is rela-tively low and only a subset of patients can benefit from the treatment. Aberrant RNA accumulation can mediate IFN signal-ing and stimulate an immune response, suggesting that targeting RNA decay machinery might sensitize tumor cells to immuno-therapy. With this in mind, we identified an RNA exoribonuclease, XRN1, as a potential therapeutic target to suppress RNA decay and stimulate antitumor immunity. Silencing of XRN1 suppress-ed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy efficacy, while silencing of XRN1 alone did not affect tumor growth in immunodeficient mice. Mechanistically, XRN1 depletion activated IFN signaling and the viral defense pathway; both pathways play determinant roles in regulating immune evasion. Aberrant RNA-sensing signaling proteins (RIG-I/MAVS) mediated the expression of IFN genes, as depletion of each of them blunted the elevation of antiviral/IFN signaling in XRN1-silenced cells. Analysis of pan-cancer CRISPR-screening data indicated that IFN signaling triggered by XRN1 silencing is a common phenomenon, suggesting that the effect of XRN1 silencing may be extended to multiple types of can-cers. Overall, XRN1 depletion triggers aberrant RNA-mediated IFN signaling, highlighting the importance of the aberrant RNA-sensing pathway in regulating immune responses. These findings provide the molecular rationale for developing XRN1 inhibitors and exploring their potential clinical application in combination with cancer immunotherapy. Significance: Targeting XRN1 activates an intracellular innate immune response mediated by RNA-sensing signaling and potenti-ates cancer immunotherapy efficacy, suggesting inhibition of RNA decay machinery as a novel strategy for cancer treatment.

Automated summary

Despite the limited response rate of immune checkpoint blockade therapy, targeting RNA decay machinery by silencing XRN1 can sensitize tumor cells to immunotherapy by activating IFN signaling and the viral defense pathway. XRN1 depletion triggers aberrant RNA-mediated IFN signaling and has the potential to be effective in multiple types of cancers. These findings provide a molecular rationale for developing XRN1 inhibitors and combining them with cancer immunotherapy.