Cyclic GMP-AMP synthase (cGAS) recognizes cytosolic DNA and catalyzes the formation of cyclic GMP-AMP, which upon activation triggers the induction of stimulator of interferon genes (STING), leading to type I interferons production; these events then promote the cross-priming of dendritic cells and the initiation of a tumor-specific CD8⁺ T cell response. However, cancer cells in the tumor microenvironment cannot trigger intrinsic cGAS-STING signaling, regardless of the expression of cGAS and STING. This dysfunctional cGAS-STING signaling enables cancer cells to evade immune surveillance, thereby promoting tumorigenesis. Here, we review recent advances in the current understanding of the activation of cGAS-STING signaling and immunotherapies based on this pathway and focus on the mechanisms for the inactivation of this pathway in tumor cells to promote the development of cancer immunotherapy. The discovery of inherent resistance and the selection of appropriate combination therapies are of great significance for tumor treatment development.