Carbohydrate Strengthens the Immunotherapeutic Effect of Small-Molecule PD-L1 Inhibitors

PD-1/PD-L1 checkpoint blockade has demonstrated great
success in
cancer immunotherapy. Small-molecule PD-L1 inhibitors also attract
significant research interests but remain challenging in the efficacy
and safety. Carbohydrate moiety and carbohydrate-binding proteins
(lectins) play important roles in immune modulation including antigen
recognition and presenting. Herein, we reported a novel strategy to
strengthen the immunotherapeutic effect of small-molecule PD-L1 inhibitors
by introducing sugar motifs, which may utilize the carbohydrate-mediated
immune enhancement for cancer treatment. The data revealed that glycoside
compounds containing mannose or N-acetylglucosamine
exhibited the best results in IFN-γ secretion. Moreover, compared
to the nonglycosylated compounds, glycosides C3 and C15 demonstrated significant lower cytotoxicity and effective
in vivo antitumor potency in the CT26 and melanoma B16-F10 tumor models
with good tolerance. Notably, tumor-infiltrating lymphocyte (TIL)
analysis validated increased CD3+, CD4+, CD8+, and granzyme B+ T cells
after glycoside treatments. This work presents a new concept to improve
the immunotherapy.