Pancreatic cancer is an aggressive malignancy that is unresponsive to 
conventional radiation and chemotherapy. Therefore, development of novel immune 
therapeutic strategies is urgently needed. L-4F, an Apolipoprotein A-I (ApoA-I) 
mimetic peptide, is engineered to mimic the anti-inflammatory and anti-oxidative 
functionalities of ApoA-I. In this work, H7 cells were orthotopically implanted 
in C57BL/6 mice and treated with L-4F. Then, pancreatic cancer progression and 
the inflammatory microenvironment were investigated in vivo. The cytotoxicity of 
L-4F toward H7 cells was assessed in vitro. Furthermore, we investigated the 
effects of L-4F on macrophage polarization by analyzing the polarization and 
genes of mouse bone marrow-derived macrophages in vitro. The results show that 
L-4F substantially reduced the tumorigenicity of H7 cells. L-4F inhibited 
inflammation by reducing the accumulation of inflammatory cells, such as 
IL-17A-, IL-4-, GM-CSF-, IL-1β-, and IL-6-producing cells and Th1 and Th17. 
Notably, L-4F also decreased the percentage of macrophages in tumor tissues, 
especially M2 macrophages (CD11b+F4/80+CD206+), which was also confirmed in 
vitro. Additionally, the expression of the M2 marker genes Arg1, MRC1, and CCL22 
and the inflammatory genes IL-6, iNOS, and IL-12 was decreased by L-4F, 
indicating that L-4F prevents M2 type macrophage polarization. However, L-4F 
could not directly attenuate H7 cell invasion or proliferation and did not 
induce apoptosis. In addition, L-4F potently down-regulated STAT3, JNK and ERK 
signaling pathways but not affects the phosphorylation of p38 in RAW 264.7 
cells. These results suggest that L-4F exhibits an effective therapeutic effect 
on pancreatic cancer progression by inhibiting tumor-associated macrophages and 
inflammation.