The innate immune sensing system plays a critical role in recognizing and responding to DNA damage, which is a key factor in cancer development and progression. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, in particular, detects cytosolic double-stranded DNA (dsDNA) and activates the innate immune response. Recent studies have shown that cGAS is sequestered on chromatin by binding to the acidic patch (AP) regions of histones. Upon DNA damage, its ability to bind to chromatin-associated dsDNA fragments requires the DNA damage sensor MRE11. Upon its activation, cGAS triggers an innate immune response that can suppress tumorigenesis. However, the context-specific factors that govern whether cGAS engagement leads to effective STING pathway activation remain incompletely defined, particularly in relation to chromatin context, micronuclear integrity, and post-translational modifications. In this review, we explore the dynamic interplay between DNA damage responses and innate immune signaling through the cGAS-STING axis, with a focus on recent mechanistic advances. We further examine how cancers evade or co-opt this pathway and highlight therapeutic opportunities to exploit cGAS-STING signaling for cancer treatment.