Dual Targeting of STING and PI3Kγ Eliminates Regulatory B Cells to Overcome STING Resistance for Pancreatic Cancer Immunotherapy
LI, C.; Mao, S.; Zhao, H.; He, M.; Wang, M.; Liu, Z.; Wen, H.; Yu, Z.; Wen, B.; Djibo, M.; Tao, J.; Bu, Y.; Gao, W.; Sun, D.
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The immune suppression in tumors and lymph nodes of pancreatic ductal adenocarcinoma (PDAC), regulated by suppressive myeloid cells and regulatory B (Breg) cells, hinders the effectiveness of immunotherapy. Although STING agonists activate myeloid cells to overcome immune suppression, it expands Breg cells, conferring STING resistance in PDAC. We discovered that blocking PI3K{gamma} during STING activation abolished IRF3 phosphorylation to eliminate Breg cells, while PI3K{gamma} inhibition sustained STING-induced IRF3 phosphorylation to preserve STING function in myeloid cells. Therefore, we developed a dual functional compound SH-273 and its albumin nanoformulation Nano-273, which stimulates STING to activate myeloid cells and inhibits PI3K{gamma} to eliminates Breg cells overcoming STING resistance. Nano-273 achieved systemic antitumor immunity through intravenous administration, which decreases Breg cells and remodels microenvironment in tumors and lymph nodes. Nano-273, combined with anti-PD-1, extended median survival to 200 days in transgenic KPC PDAC mice (KrasG12D-P53R172H-Cre), offering potential for PDAC treatment.
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