Cytosolic nucleic acid sensing, an early event of host defense initiation, are encouraging therapeutic targets to inflame tumor microenvironments. Although the signaling transduction is well documented, the physiological function of cytosolic nucleic acid sensing in tumor microenvironments remains poorly known. Our interest is to discover the novel role and regulator of cytosolic nucleic acid sensing in different settings such as radiotherapy and immunotherapy. Based on our mechanism findings in animal models and clinical samples, our goal is to develop new combination strategies to improve radiotherapy and immunotherapy and then translate them into clinic to benefit cancer patients.