Inhibiting autophagy to boost antitumor immunity with tetramethylpyrazine-loaded and PD-L1-targeting liposomal nanoparticles

Cancer immunotherapy has been recognized as a revolutionary breakthrough and has yielded impressive results. However, a major challenge facing immunotherapy is its limited efficacy, which may be largely due to the inadequate infiltration of immune cells into the tumor microenvironment (TME). Autophagy inhibition has been identified to enhance the recruitment of immune cells into the tumor by upregulating the expression and secretion of chemokines. Here, we verified a novel autophagy inhibitor tetramethylpyrazine (TMP) from natural products using a mCherry-GFP-LC3 probe-based autophagy flux reporter system. We then devised a liposomal system capable of co-delivering DOX and TMP using the thin-film dispersion method and modified the liposome with PD-L1 binding peptide JY4 (DOX-TMP-JY4LIPO). We found that DOX-TMP-JY4LIPO exhibited potent antitumor efficacy in vitro. In addition, DOX-TMP-JY4LIPO could effectively inhibit the autophagic flux to enhance the recruitment of immune cells into the tumor by upregulating CCL5 and CXCL10. The liposome exhibited favorable biocompatibility and safety while facilitating the accumulation of therapeutic drugs in tumors. DOX-TMP-JY4LIPO significantly inhibited tumor growth in LLC xenograft mice, accompanied by increased granzymes- and perforin-mediated cytotoxic immune responses. Our findings demonstrate that the TMP-loaded and PD-L1-targeting liposomal nanoparticles can significantly boost antitumor immunity by inhibiting autophagy, suggesting a novel natural product-based nanomedicine for immunotherapy.