TLR9 activation of STAT3 constrains its agonist-based immunotherapy
Although toll-like receptor (TLR) agonists, such as CpG, are used as immunotherapeutic agents in clinical trials for cancer and infectious diseases, their effects are limited and the underlying mechanism(s) that restrains CpG efficacy remains obscure. Here we demonstrate that signal transducer and activator of transcription 3 (Stat3) plays a key role in downmodulating CpG’s immunostimulatory […]
Regulation of the IL-23 and IL-12 balance by STAT3 signaling in the tumor microenvironment
Interactions between tumor and immune cells either enhance or inhibit cancer progression. We show here that Stat3 signaling within the tumor microenvironment induces a procarcinogenic cytokine, IL-23, while inhibiting a central anticarcinogenic cytokine, IL-12, thereby shifting the balance of tumor immunity toward carcinogenesis. Stat3 induces expression of IL-23, which is mainly produced by tumor-associated macrophages, […]
Crosstalk between cancer and immune cells: role of STAT3 in the tumor microenvironment
Immune cells in the tumour microenvironment not only fail to mount an effective anti-tumour immune response, but also interact intimately with the transformed cells to promote oncogenesis actively. Signal transducer and activator of transcription 3 (STAT3), which is a point of convergence for numerous oncogenic signalling pathways, is constitutively activated both in tumour cells and […]
Inhibiting STAT3 signaling in the hematopoietic system elicits multicomponent antitumor immunity
The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells […]
Regulation of the innate and adaptive immune responses by Stat3 signaling in tumor cells
Although tumor progression involves processes such as tissue invasion that can activate inflammatory responses, the immune system largely ignores or tolerates disseminated cancers. The mechanisms that block initiation of immune responses during cancer development are poorly understood. We report here that constitutive activation of Stat-3, a common oncogenic signaling pathway, suppresses tumor expression of proinflammatory […]
STAT3 inhibition combined with CpG immunostimulation activates antitumor immunity to eradicate genetically distinct castration-resistant prostate cancers
Prostate cancers have proven resilient to emerging clinical immunotherapies, including cancer vaccines and immune checkpoint blockade. Growing evidence emphasizes the role of the tolerogenic tumor microenvironment, with the essential role of STAT3 signaling in myeloid cells, in shielding prostate cancers from antitumor immunity. Here, we describe new bifunctional CpG-STAT3ASO molecules, which trigger Toll-like Receptor 9 […]
