Dual targeting of PI3Kgamma and STING overcomes regulatory B cell- and myeloid cell-driven immune suppression in pancreatic cancer
Menée à l'aide d'organoïdes et de modèles murins de cancer du pancréas, cette étude met en évidence l'intérêt d'un composé à base d'albumine ciblant la kinase PI3Kgamma et la protéine STING pour lever l'immunosuppression induite par les lymphocytes B régulateurs et les cellules myéloïdes
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 PI3Kgamma
but not PI3K
delta
in pancreatic cancer, whereas activating myeloid cells were independent of PI3K
gamma
. Inhibition of PI3Kγ, but not PI3K
delta
, 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 PI3K
gamma
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.
Nature Cancer , article en libre accès, 2026