Leveraging the crosstalk between cGAS-STING and pyroptosis by nanomedicine to enhance antitumor immunity.

The cGAS-STING pathway and pyroptosis represent two potent immunostimulatory mechanisms with immense potential for cancer therapy. cGAS-STING activation drives type I interferon production and dendritic cell maturation, while pyroptosis, a form of inflammatory programmed cell death, releases tumor antigens and damage-associated molecular patterns (DAMPs) that recruit and activate immune cells. However, their clinical translation is hampered by issues such as poor bioavailability, systemic toxicity, and inefficient tumor-specific delivery. Nanomedicine has emerged as a transformative strategy to overcome these barriers and harness the synergistic interplay between these pathways to profoundly enhance antitumor immunity. By enabling precise co-delivery of agonists, inducing mitochondrial damage, and incorporating immunostimulatory metal ions (e.g., Mn²⁺, Co²⁺), engineered nanoplatforms can simultaneously or sequentially activate cGAS-STING signaling and trigger gasdermin-mediated pyroptosis. This coordinated activation establishes a self-reinforcing cycle: pyroptosis releases cytosolic DNA (e.g., mtDNA) that activates cGAS-STING, whose downstream cytokines further potentiate inflammatory cell death. The resultant cascade remodels the tumor microenvironment, converting immunologically “cold” tumors into “hot” ones by promoting dendritic cell maturation, enhancing cytotoxic T lymphocyte infiltration, and reversing immunosuppression. This review synthesizes recent advances in nano-designed strategies that exploit the cGAS-STING-pyroptosis axis, highlighting how nanomedicines are uniquely positioned to amplify antitumor immunity, overcome resistance to conventional immunotherapies, and pave the way for next-generation combination cancer treatments.