Unlocking the therapeutic potential of the STING signaling pathway in anti-tumor treatment.

The STING signaling pathway, as a core hub connecting innate immunity and adaptive immunity, plays a complex and dynamic dual role in tumor immune regulation. This review systematically explains the multi-dimensional mechanism of this pathway in tumor occurrence and development: On the one hand, it builds a multi-level anti-tumor immune response network by activating the antigen presentation function of dendritic cells (DCs), enhancing the stemness maintenance of CD8⁺ T cells and the cytotoxic effect of natural killer cells (NK cells); on the other hand, it forms a bidirectional regulation with the malignant transformation process of tumors (such as epithelial-mesenchymal transition (EMT), angiogenesis, and metabolic reprogramming), and its direction of action highly depends on the spatiotemporal specificity of the tumor microenvironment and the level of genomic instability. Research reveals that the anti-tumor efficacy of the STING pathway is precisely regulated by the intensity of DNA damage response (DDR), mitochondrial stress state, and epigenetic regulatory network (such as the yes-associated protein/transcriptional coactivator with PDZ-binding motif-protein phosphatase 2A catalytic subunit (YAP/TAZ-PP2Ac) axis, which provides a molecular basis for the development of precise intervention strategies. Current combined treatment strategies have broken through the limitation of single-target, achieving multi-level synergy from molecular intervention to system regulation through the sequential coordination of immune checkpoint inhibitors and STING agonists, the positive feedback loop of DNA damage induced by radiotherapy (RT)/chemotherapy and innate immune activation, and tumor metabolic-immune reprogramming mediated by nanocarriers. Notably, STING activation may induce the compensatory upregulation of immune suppressive factors such as interleukin-35 (IL-35)/programmed cell death 1 ligand 1 (PD-L1), and stratified treatment strategies based on tumor heterogeneity characteristics will become the key to overcoming drug resistance. This article not only constructs a theoretical framework of "immune initiation-microenvironment remodeling-malignant transformation inhibition" in a trinity, but also marks the paradigm shift of tumor immunotherapy from single-pathway activation to multi-scale dynamic regulation, providing a route map that is both innovative and feasible for clinical translation.