Abstract The cGAS-STING pathway is a central regulator of innate immunity and exhibits a complex dual function in lung cancer: it can activate anti-tumor immune responses but also promote immune escape and metastasis. This “double-edged sword” effect is highly dependent on the spatiotemporal heterogeneity of the tumor microenvironment (TME), referring to dynamic changes in immune and metabolic features across different regions and disease stages. To optimize existing therapies, overcome resistance, and develop novel treatments to improve patient outcomes, it is crucial to deeply understand the interaction between the TME and the cGAS-STING pathway. This review systematically discusses the pro-tumor and anti-tumor mechanisms of the cGAS-STING pathway in lung cancer; the modulation of cGAS-STING pathway activity by TME spatiotemporal heterogeneity, via the dynamic interplay of distinct cell types and physicochemical gradients; and cGAS-STING-driven precision immunotherapy and artificial intelligence (AI) optimization. Integrating TME spatiotemporal heterogeneity, immunometabolism crosstalk, with cGAS-STING pathway function may provide new insights for improving therapeutic strategies, reversing resistance, and enhancing survival outcomes for lung cancer patients. Graphical Abstract
Ye et al. (Sat,) studied this question.