Dual targeting of PI3Kγ and STING overcomes regulatory B cell- and myeloid cell-driven immune suppression in pancreatic cancer.

Both regulatory B (Breg) and myeloid cells in tumors and lymph nodes drive immune suppression in pancreatic cancer. Current strategies to counter immune suppression emphasize myeloid cells but overlook Breg cells. We discovered that STING agonist expanded Breg cells depended on PI3Kγ but not PI3Kδ in pancreatic cancer, whereas activating myeloid cells were independent of PI3Kγ. Inhibition of PI3Kγ, but not PI3Kδ, decreased STING-induced IRF3 phosphorylation and Breg cell expansion in pancreatic cancer, while sustaining STING-induced IRF3 phosphorylation to activate myeloid cells. We developed a dual targeting compound and its albumin nanoformulation Nano-273, which stimulated STING to activate myeloid cells and inhibited PI3Kγ to decrease STING-induced Breg cell expansion. Nano-273 delivered the drug to tumors and lymph nodes to overcome myeloid cell- and Breg cell-mediated immune suppression in pancreatic cancer. Nano-273, combined with anti-programmed cell death protein 1, achieved durable efficacy in transgenic KPC mice with pancreatic cancer, offering potential for pancreatic cancer treatment.