The cGAS-STING pathway in the tumor immune microenvironment: Multidimensional regulation and therapeutic implications

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a prominent target in cancer immunotherapy. The highly heterogeneous and dynamically plastic nature of the tumor immune microenvironment (TIME) dictates the outcomes of immunotherapeutic interventions. Although the cGAS-STING pathway has been extensively studied in tumor immunity, current reviews predominantly focus on canonical linear signaling or cell-autonomous functions within isolated immune or tumor cell types, thereby failing to establish an integrated mechanistic framework that accounts for coordinated crosstalk among malignant, immune, and stromal compartments. Here, we move beyond the conventional paradigm of ligand-dependent, cell-intrinsic STING activation and instead adopt a systems-level perspective grounded in spatiotemporal context and dynamic regulation. We systematically delineate how cGAS-STING activity exerts context-dependent, non-cell-autonomous effects across the multicellular TIME network-functioning not as a generic immune amplifier, but as a regulatory axis that orchestrates immune-ecological reconfiguration of the microenvironment. Accordingly, we argue that next-generation therapeutic strategies should transition from indiscriminate pathway activation toward precision-targeted intervention and microenvironmental reprogramming-thereby enabling rational design of more effective and durable cancer immunotherapies.