Advances in STING Pathway Modulation for Cancer and Immunotherapy: A Comprehensive Review of Preclinical and Clinical Studies (2020–2024)

In cancer immunotherapy, the stimulator of interferon genes (STING) pathway regulation has become a promising new approach, offering potential solutions to overcome limitations of current treatments. Recent advances have revealed intricate mechanisms of STING activation and regulation, leading to the development of novel small-molecule agonists with improved properties. Preclinical studies have shown that STING agonists can convert "cold" tumors to "hot" ones, enhancing immune cell infiltration and overcoming resistance to checkpoint inhibitors. Combination strategies, particularly with existing immunotherapies and conventional treatments, have demonstrated synergistic effects. Early clinical trials evaluating STING agonists, both as monotherapies and in combination with checkpoint inhibitors, have yielded promising results. More specific methods have been made possible by biomarker investigations, which have revealed light on mechanisms of action and possible response predictors. Indirect STING activation through ENPP1 inhibition has emerged as a novel strategy, offering more controlled antitumor immunity enhancement while minimizing systemic toxicity. Innovative delivery systems, including nanoparticles and exosome-based therapies, improve STING modulators' therapeutic index. While challenges remain, including precise regulation of STING activation and managing immune-related adverse events, rapid progress suggests that STING-targeted therapies could become cornerstone treatments. By harnessing innate immunity and enhancing its interplay with adaptive responses, STING modulators offer a potentially more accessible, cost-effective, and broadly applicable approach to cancer immunotherapy, addressing many current treatment limitations.