STING activation in macrophages by vanillic acid exhibits antineoplastic potential

The human immune system is responsible for differentiating between self and non-self, and protects the body from attacks by pathogens and damaged or abnormal cells [1]. Although immunotherapy including immune checkpoint blockade therapy and CAR T cell adoptive immunotherapy has been established as a promising approach for tumor treatment, a limited number of patients are suitable for such therapy. A large number of patients are refractory to the therapy or relapse after the therapy. Therefore, there is a need to develop more effective immunotherapy [2], [3], [4].

The stimulator of interferon genes (STING, also known as TMEM173) is a cytoplasmic DNA sensor which plays a critical role not only in host defense against pathogens, but also in anti-tumor immunity [5]. Upon recognition of pathogenic or mislocated self-DNA, cyclic GMP-AMP (cGAMP) synthase (cGAS) catalyzes the production of cyclic dinucleotide cGAMP which binds to and activates STING in the endoplasmic reticulum (ER). Following activation and oligomerization, STING undergoes conformational changes and translocates to the ER-Golgi intermediate compartments. Activated STING recruits and activates TANK-binding kinase 1 (TBK1), followed by the recruitment and phosphorylation of IFN regulatory factor 3 (IRF3). The phosphorylated IRF3 translocates to the nucleus to trigger the expression of type I IFN and other immune-stimulated genes (such as CXCL9, and CXCL10) [6], [7], [8]. In parallel, STING activates the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway, which collaborates with the TBK1-IRF3 pathway to induce the production of type I IFN [8], [9]. The type I IFN signature is associated with tumor regression through immune cell stimulation. Decreased STING activity or expression has been found to lead to immune evasion in many tumor tissues [10], [11]. A study of seventeen different histological types of tumors revealed significant heterogeneity in STING expression among the tumors [12]. A study in mice with neck squamous cell carcinoma indicated that the inhibition of cGAS-STING signaling results in reduced numbers of tumor-infiltrating CD3 + CD8 + cells and decreased type I IFN [13]. In glioma and gastric cancer, reduced STING activity in tumors prevents immune cell-mediated apoptosis of tumor cells [14], [15]. These observations indicate that cGAS-STING activation is a potential therapeutic strategy for cancer immunotherapy.

It is widely accepted that macrophages are potent immune effector cells that display plastic characteristics with reference to tumor development in various settings including clearance of cellular debris and pathogens and the regulation of inflammatory responses [16], [17]. Depending on the stimulus, macrophages can be polarized into either of two phenotypes with opposite functions. Alternatively activated (or wound-healing) M2 macrophages (M2 phenotype) exhibit anti-inflammatory characteristics and express Arg-1, IL10, and TGFβ which mediate tumor immunosuppression, angiogenesis, and metastasis [16]. Tumor-associated macrophages (TAMs) exhibit the M2 phenotype, and thus inhibit endogenous antitumor immunity and enhance tumor angiogenesis and metastasis. In contrast, classically activated (or inflammatory) M1 macrophages (M1 phenotype) exhibit pro-inflammatory responses by secreting TNF-α, IL1β, and iNOS. These molecules modulate the host defense against pathogens and participate in antitumor immunity [18], [19]. Hence, reducing the levels of M2 macrophages and increasing those of M1 macrophages has been regarded as an effective anti-cancer strategy. Recently, emerging evidence has shown that the activation of the cGAS/STING pathway promotes macrophage polarization into the M1 phenotype. A study on prostate cancer revealed that STING knockout reduced the rate of macrophage phagocytosis [20]. It has been found that cGAMP-induced STING activation led to the polarization of macrophages to the pro-inflammatory phenotype and mediated tumor cell apoptosis in gastric cancer [14]. Collectively, these findings suggest that STING activation in macrophages may be an effective approach for tumor immunotherapy.

Vanillic acid (VA) is an aromatic acid extracted from numerous medicinal plants such as Angelica sinensis and Panax ginseng. VA has been reported to promote favorable outcomes in various disease models due to its powerful antioxidant and antimicrobial properties [21], [22]. Recent studies have reported its anticancer properties in several types of cancers including melanoma, prostate cancer, and lung cancer [23], [24]. However, a connection between STING-related anti-tumor activity and VA has not been explored. In this study, VA was found to activate the STING/TBK1/IRF3 pathway in macrophages, subsequently exerting anti-tumor effects against breast and lung carcinoma cells through IFNβ and IL6R/JAK signaling.

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