Cationic polysaccharide spermine-pullulan drives tumor associated macrophage towards M1 phenotype to inhibit tumor...

Macrophages are predominant immune cells in the tumor microenvironment where they display an immunosuppressive M2 phenotype to support tumor growth. Reprogramming M2-like tumor-associated macrophages (TAMs) to antitumor M1 phenotype represents as a promising strategy in cancer immunotherapy. In this work we reported that one cationic polysaccharide spermine modified pullulan (PS) could act as an effective immunological stimulator to modulating either naïve (M0) or M2 macrophages towards M1 phenotype. We showed that PS upregulated the expression of TLR1/3/4 and promoted the phosphorylation of Akt, Erk, JNK, following the activation of NF-κB, which led to the polarization towards M1. In a murine breast cancer model of tumor cell 4T1 inoculation, subcutaneous injection of PS induced effective antitumor effect through reprogramming M2 macrophages in the tumor microenvironment to M1, increased CD4⁺ and CD8⁺ T cells, and decreased the expression of CD31 in the tumor mass, which together inhibited the tumor progression and the metastasis in lung and liver, leading to the prolong of the mice survival. In conclusion, PS could effectively stimulate the immunological function of macrophages. Therefore, PS may provide a novel immunological stimulator to cancer immune therapies.