Integrating STING activation with programmed death-ligand 1 inhibition: Novel approaches for cancer treatment

Immune checkpoint inhibitors (ICIs), including programmed cell death protein-1 (PD-1)/PD-L1 blockade, have transformed cancer therapy; however, primary resistance, limited response durability, and heterogeneous clinical outcomes remain significant challenges. The stimulator of interferon genes (STING) pathway, a central regulator of innate-adaptive immune crosstalk, has emerged as a promising yet biologically complex target in cancer immunotherapy. Acute STING activation enhances type I interferon (IFN-I) production, dendritic cell (DC) maturation, and cytotoxic T lymphocyte (CTL) infiltration, whereas sustained or dysregulated signaling can induce PD-L1 expression and promote immunosuppressive programs within the tumor microenvironment. Preclinical studies demonstrate that a rational combination of STING agonists with PD-1/PD-L1 inhibitors can reprogram the tumor microenvironment, enhance antigen presentation, and improve antitumor immune activity in experimental models. In contrast, early-phase clinical trials of STING agonists, including ADU-S100, SYNB1891, IMSA101, and MK-1454, have shown acceptable safety and pathway engagement but generally modest and variable clinical responses, primarily reflected by low objective response rates and limited disease stabilization. These outcomes highlight the context-dependent nature of therapeutic efficacy and the gap between preclinical expectations and current clinical results. This review synthesizes mechanistic, translational, and clinical evidence to critically evaluate both the therapeutic potential and inherent risks of STING/PD-1/PD-L1 combination strategies. We highlight emerging drug delivery platforms, such as nanocarriers, antibody-drug conjugates, and exosome-based systems, as key modulators of efficacy and safety, and emphasize the importance of biomarker-guided approaches for patient stratification and trial optimization. By integrating biological insight with translational feasibility, this review provides a framework for advancing STING-based combination immunotherapy toward more durable and personalized cancer treatment.