STING-Activating Nanoparticles Combined with PD-1/PD-L1 Blockade: A Synergistic Approach in Cancer Immunotherapy

Abstract

Objectives: Immunotherapy combining agonists of the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway with PD-1/PD-L1 blockade shows promising preclinical results, although in clinical practice, it faces pharmacokinetic barriers, systemic toxicity, and an immunosuppressive tumor microenvironment (TME). Recent advances in and expansion of the cGAS-STING pathway as a therapeutic target have further highlighted its central role in innate and adaptive immune activation. The aim of this paper is to review combination strategies of STING and PD-1/PD-L1 checkpoint blockade therapies, triple-therapy strategies using a third component such as chemotherapy, radiotherapy, photodynamic therapy (PDT), and others, and the use of nanoparticles as carriers for these drugs. Methods: Reports in the literature on the mechanisms of STING + PD-1/PD-L1 synergy, as well as with the use of a third component and delivery systems, were analyzed. Current challenges and limitations, as well as prospects for the development of these therapies, are noted. Results: Activation of the cGAS-STING synergizes with blocking the PD-1/PD-L1 axis. The addition of a third component further enhances the anti-tumor effect through a stronger induction of immunogenic cell death (ICD), increased production of interferons and pro-inflammatory cytokines, repolarization of macrophages, and enhanced infiltration of T lymphocytes. Conclusions: Therapy with STING agonists and PD-1/PD-L1 checkpoint inhibitors, supported by nanotechnology vehicles and using a third therapeutic component, overcomes key pharmacological and immunological limitations. This multimodal immunotherapeutic strategy holds high translational promise, offering more effective and safer solutions in cancer immunotherapy.

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