Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers

BACKGROUND: Our previous work showed that the anti-TGF-β/PD-L1 bispecific antibody YM101 effectively overcame anti-PD-L1 resistance in immune-excluded tumor models. However, in immune-desert models, the efficacy of YM101 was limited. Bivalent manganese (Mn(2+)) is identified as a natural stimulator of interferon genes (STING) agonist, which might enhance cancer antigen presentation and improve the therapeutic effect of YM101. METHODS: The effect of Mn(2+) on STING pathway was validated by western blotting and enzyme-linked immunosorbent assay. Dendritic cell (DC) maturation was measured by flow cytometry. The synergistic effect between Mn(2+) and YM101 in vitro was determined by one-way mixed lymphocyte reaction, CFSE dilution assay, and cytokine detection. The in vivo antitumor effect of Mn(2+) plus YM101 therapy was assessed in CT26, EMT-6, H22, and B16 tumor models. Flow cytometry, RNA-seq, and immunofluorescent staining were adopted to investigate the alterations in the tumor microenvironment. RESULTS: Mn(2+) could activate STING pathway and promote the maturation of human and murine DC. The results of one-way mixed lymphocyte reaction showed that Mn(2+) synergized YM101 in T cell activation. Moreover, in multiple syngeneic murine tumor models, Mn(2+) plus YM101 therapy exhibited a durable antitumor effect and prolonged the survival of tumor-bearing mice. Relative to YM101 monotherapy and Mn(2+) plus anti-PD-L1 therapy, Mn(2+) plus YM101 treatment had a more powerful antitumor effect and a broader antitumor spectrum. Mechanistically, Mn(2+) plus YM101 strategy simultaneously regulated multiple components in the antitumor immunity and drove the shift from immune-excluded or immune-desert to immune-inflamed tumors. The investigation in the TME indicated Mn(2+) plus YM101 strategy activated innate and adaptive immunity, enhanced cancer antigen presentation, and upregulated the density and function of tumor-infiltrating lymphocytes. This normalized TME and reinvigorated antitumor immunity contributed to the superior antitumor effect of the combination therapy. CONCLUSION: Combining Mn(2+) with YM101 has a synergistic antitumor effect, effectively controlling tumor growth and prolonging the survival of tumor-bearing mice. This novel cocktail strategy has the potential to be a universal regimen for inflamed and non-inflamed tumors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-021-01155-6.