A flexible antigen-presenting cell targeting lentinan immunomodulator promotes stimulator of interferon gene-driven...

Activation of antigen-presenting cells (APCs) via the stimulator of interferon genes (STING) signaling pathway is a promising strategy for cancer therapy. However, the rational engineering of a targeted synergistic immunomodulator and its morphological impact for STING activation remains elusive. Herein, we developed an APC-targeting lentinan-STING agonist immunomodulator with flexible and assembled morphological forms for cancer therapy. Lentinan (LN) exhibited intrinsic APC targeting and immune activation characteristics, and the conjugation between lentinan and a STING agonist (DMXAA) not only decreased the toxicity of lentinan toward APC cells, but also realized synergistic STING activation via lentinan and DMXAA. The flexible and assembled morphological forms were readily achieved by tuning the DMXAA loadings of the immunomodulators, denoted as LN-DMXAA(L) and LN-DMXAA(H). The flexible immunomodulator LN-DMXAA(L) with lower DMXAA loading potently induced macrophage reprogramming and dendritic cell maturation as compared with the assembled immunomodulator LN-DMXAA(H) and free drug DMXAA. In a 4 T1 tumor-bearing mice model, LN-DMXAA(L) significantly boosted tumor growth inhibition rate to 78.3% as compared with 46.2% for LN-DMXAA(H) and 27.8% for DMXAA by activating APCs and CD8⁺ T cells via the STING signaling pathway. Thus, this work highlights the conception of a flexible immune-activating polysaccharide-STING agonist immunomodulator for cancer therapy.