Targeting STING signaling for the optimal cancer immunotherapy

Abstract

Despite the transformative impact of anti-PD-1/PD-L1 therapies, challenges such as low response rates persist. The stimulator of interferon genes (STING) pathway, a crucial element of innate immunity, emerges as a strategic target to overcome these limitations. Understanding its multifaceted functions in cancer, including antigen presentation and response to DNA damage, provides valuable insights. STING agonists, categorized into cyclic dinucleotides (CDNs) and non-CDNs, exhibit promising safety and efficacy profiles. Innovative delivery systems, including antibody-drug conjugates, nanocarriers, and exosome-based therapies, address challenges associated with systemic administration and enhance targeted tumor delivery. Personalized vaccines, such as DT-Exo-STING, showcase the adaptability of STING agonists for individualized treatment. These advancements not only offer new prospects for combination therapies but also pave the way for overcoming resistance mechanisms. This review focuses on the potential of targeting STING pathway to enhance cancer immunotherapy. The integration of STING agonists into cancer immunotherapy holds promise for more effective, personalized, and successful approaches against malignancies, presenting a beacon of hope for the future of cancer treatment.

Keywords: PD-1; PD-L1; STING; cancer immunotherapy; the tumor microenvironment.

Figure 1

The STING signaling pathway. Activated STING undergoes conformational changes, engaging TBK1 and IRF3. TBK1, forming a homodimer, interacts with two STING molecules, inducing a conformational shift that releases the C-terminal tail of STING. This enables recruitment and activation of TBK1, leading to phosphorylation of serine 366 of the STING C-terminal tail. Phosphorylated IRF3 undergoes homodimerization, translocates to the nucleus, and triggers the transcription of type I interferon (IFN) and other interferon-stimulated genes (ISGs). The STING-TBK1-IRF3 axis acts as a critical link in antiviral defense, orchestrating IFN production to curb viral replication and spread. Importantly, the STING-TBK1-IRF3 pathway also intersects with canonical NF-κB signaling (Created with Biorender).

Figure 2

The STING signaling in dendritic cells (DCs). The STING pathway in DCs plays a vital role by taking up tumor-derived DNA, leading to increased type I IFN expression. This enhances DC cross-presentation, survival, lymph node homing, and the expression of Th1 chemokines, crucial for immune cell trafficking (Created with Biorender).