Nanomaterial-encapsulated STING agonists for immune modulation in cancer therapy Xi Chen, Zhijie Xu, Tongfei Li, Abhimanyu Thakur, Yu Wen, Kui Zhang, Yuanhong Liu, Qiuju Liang, Wangrui Liu, Jiang-Jiang Qin, and Yuanliang Yan Abstract: The cGAS-STING signaling pathway plays a critical role in innate immune responses and improving antitumor immunity. Targeting this pathway can overcome immunosuppressive tumor microenvironments (TME) and promote effective tumor elimination. However, systemic administration of current STING agonists faces challenges related to low bioavailability and potential adverse effects, limiting their clinical applicability. Recent advances in nanotechnology have enabled the encapsulation and delivery of STING agonists within nanoparticles (STING-NPs), offering an attractive avenue for antitumor immunotherapy. This review explores various nanoparticles designed to encapsulate STING agonists, highlighting their benefits, including favorable biocompatibility, improved tumor penetration, and efficient intracellular delivery of STING agonists. The review also summarizes the immunomodulatory impacts of STING-NPs on the TME, including enhanced secretion of pro-inflammatory cytokines and chemokines, dendritic cell activation, cytotoxic T cell priming, macrophage re-education, and vasculature normalization. Furthermore, the review offers insights into co-delivered nanoplatforms involving STING agonists alongside antitumor agents such as chemotherapeutic compounds, immune checkpoint inhibitors, antigen peptides, and other immune adjuvants. These platforms demonstrate remarkable versatility in inducing immunogenic responses within the TME, ultimately amplifying the potential for antitumor immunotherapy. Keywords: cGAS-STING pathways, STING agonists, Nanoparticles, Cancer immunotherapy Introduction: Immunotherapy has emerged as a promising option for several advanced and refractory tumors. However, the success of immunotherapy is still limited, mainly due to insufficient immune responses. A common obstacle to effective cancer immunotherapy is the presence of an immunosuppressive tumor microenvironment (TME). The TME is a complex entity consisting of immune cells, fibroblasts, endothelial cells, vasculature, cytokines, and chemokines. These components interact with tumor cells and are critical in tumor progression and therapeutic effects. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a crucial player in cancer immunity. Activation of the STING signaling pathway can stimulate innate inflammatory immune responses and potentially overcome immunosuppression in TME. In particular, STING activation can induce DC activity, leading to infiltration of IFN-γ-producing T cells in colorectal cancers. Furthermore, STING-mediated type I interferon signaling amplifies the stem cell-like CD8+Nanomaterial-encapsulated STING agonists for immune modulation in cancer therapy Xi Chen, Zhijie Xu, Tongfei Li, Abhimanyu Thakur, Yu Wen, Kui Zhang, Yuanhong Liu, Qiuju Liang, Wangrui Liu, Jiang-Jiang Qin, and Yuanliang Yan Abstract: The cGAS-STING signaling pathway plays a critical role in innate immune responses and improving antitumor immunity. Targeting this pathway can overcome immunosuppressive tumor microenvironments (TME) and promote effective tumor elimination. However, systemic administration of current STING agonists faces challenges related to low bioavailability and potential adverse effects, limiting their clinical applicability. Recent advances in nanotechnology have enabled the encapsulation and delivery of STING agonists within nanoparticles (STING-NPs), offering an attractive avenue for antitumor immunotherapy. This review explores various nanoparticles designed to encapsulate STING agonists, highlighting their benefits, including favorable biocompatibility, improved tumor penetration, and efficient intracellular delivery of STING agonists. The review also summarizes the immunomodulatory impacts of STING-NPs on the TME, including enhanced secretion of pro-inflammatory cytokines and chemokines, dendritic cell activation, cytotoxic T cell priming, macrophage re-education, and vasculature normalization. Furthermore, the review offers insights into co-delivered nanoplatforms involving STING agonists alongside antitumor agents such as chemotherapeutic compounds, immune checkpoint inhibitors, antigen peptides, and other immune adjuvants. These platforms demonstrate remarkable versatility in inducing immunogenic responses within the TME, ultimately amplifying the potential for antitumor immunotherapy. Keywords: cGAS-STING pathways, STING agonists, Nanoparticles, Cancer immunotherapy Introduction: Immunotherapy has emerged as a promising option for several advanced and refractory tumors. However, the success of immunotherapy is still limited, mainly due to insufficient immune responses. A common obstacle to effective cancer immunotherapy is the presence of an immunosuppressive tumor microenvironment (TME). The TME is a complex entity consisting of immune cells, fibroblasts, endothelial cells, vasculature, cytokines, and chemokines. These components interact with tumor cells and are critical in tumor progression and therapeutic effects. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a crucial player in cancer immunity. Activation of the STING signaling pathway can stimulate innate inflammatory immune responses and potentially overcome immunosuppression in TME. In particular, STING activation can induce DC activity, leading to infiltration of IFN-γ-producing T cells in colorectal cancers. Furthermore, STING-mediated type I interferon signaling amplifies the stem cell-like CD8+