The cGAS-STING pathway in cancer immunity: dual roles, therapeutic strategies, and clinical challenges

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a crucial component of the host's innate immunity and plays a central role in detecting cytosolic double-stranded DNA from endogenous and exogenous sources. Upon activation, cGAS synthesizes cGAMP, which binds to STING, triggering a cascade of immune responses, including the production of type I interferons and pro-inflammatory cytokines. In the context of cancers, the cGAS-STING pathway can exert dual roles: on the one hand, it promotes anti-tumor immunity by enhancing antigen presentation, stimulating T-cell responses, and inducing direct tumor cell apoptosis. On the other hand, chronic activation, particularly in tumors with chromosomal instability, can lead to immune suppression and tumor progression. Persistent cGAS-STING signaling results in the up-regulation of immune checkpoint molecules such as PD-L1, contributing to immune evasion and metastasis. Consequently, anti-tumor strategies targeting the cGAS-STING pathway have to consider the balance of immune activation and the immune tolerance caused by chronic activation. This review explores the mechanisms underlying both the anti-tumor and protumor roles of the cGAS-STING pathway, with a focus on potential therapeutic approaches, and the challenges faced in their clinical application, along with corresponding solutions.