Inflammatory bowel disease (IBD), a prevalent chronic inflammatory disorder with unsatisfactory therapeutic outcomes, significantly increases the risk of colorectal cancer. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon gene (STING), highly expressed in human IBD, are potential anti-inflammatory and anti-tumor immunotherapeutic targets. However, conflicting evidence regarding the dual roles of the STING pathway has significantly hindered its development as a therapeutic target for innovative treatments. Previous studies have predominantly suggested that hyperactivation of the STING pathway contributes to colitis development, while simultaneously enhancing anti-tumor immunity and inhibiting cancer progression. On the other hand, specific contexts, such as STING deficiency in T cells or prolonged, excessive STING activation within tumors, paradoxically promote disease progression. We also thoroughly analyzed the origin of STING activation in these diseases to offer insights into the identification of novel druggable targets. Crucially, “cell context-dependency, treatment timing and duration, and biased signal transduction” are likely the mechanistic basis underlying STING pathway’s dual roles, proposing spatiotemporal-specific STING modulators as future therapeutics.