Low-dose arsenic trioxide inhibits pancreatic stellate cell activation via LOXL3 expression to enhance immunotherapy in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is characterized by abnormally fibrotic mesenchyme, which notably influences on the effectiveness of immunotherapy. Low-dose arsenic trioxide (ATO, 1.0 μM) can inhibit the activation of pancreatic stellate cells (PSCs) and affect fibrosis, which is a potential strategy for enhancing the sensitivity to immunotherapy. METHODS: Extracellular matrix (ECM) models were employed to assess the regulatory effects of ATO on ECM and peripheral blood mononuclear cells. Orthotopic C57BL/6J models were utilized to evaluate the influence of ATO on CD8(+)T cell infiltration and immunotherapy in PC. Additionally, nanomaterials loaded with ATO designed to specifically target PSCs (scAbFAP-α-HMSNs-PAA-ATO) were produced to enhance targeting effects of ATO. RESULTS: Low-dose ATO (1.0 μM) suppressed PSCs activation, exhibiting potential for synergistic immunotherapy. Under low-dose ATO intervention, ECM underwent remodeling, leading to increases in CD8(+)T cell infiltration, thereby enhancing anti-PD-L1 therapy effect. We further demonstrated that low-dose ATO remodeled ECM by regulating the expression of LOXL3 in PSCs. scAbFAP-α-HMSNs-PAA-ATO exhibited improved targeting capabilities, and enhanced capacity to inhibit fibrosis and sensitize immunotherapy. CONCLUSIONS: Our research reveals that low-dose ATO, by regulating LOXL3, remodels the ECM and enhances CD8(+)T cell infiltration, thus sensitizing the efficacy of immunotherapy, which provides a novel strategy for comprehensive treatment to PC.