Combination of oral STING agonist MSA-2 and anti-TGF-beta/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors

Non-inflamed tumors, including immune-excluded and immune-desert tumors, are commonly resistant to anti-PD-1/PD-L1 therapy. Our previous study reported the potent antitumor activity of anti-TGF-beta/PD-L1 bispecific antibody YM101 in immune-excluded tumors. However, YM101 had limited antitumor activity in immune-desert models. MSA-2 is a novel oral stimulator of interferon genes (STING) agonist, which activates the innate immune system and may synergize with YM101 in overcoming immunotherapy resistance. In this work, we found MSA-2 could promote the maturation and antigen presentation capability of murine dendritic cell. In the one-way mixed lymphocyte reaction assay, MSA-2 synergized with YM101 in enhancing naive T cell activation. Moreover, MSA-2 stimulated the classical activation of macrophage, without significant influence on alternative activation. Further in vivo explorations showed that MSA-2 increased multiple proinflammatory cytokines and chemokines in the tumor microenvironment. MSA-2 combined with YM101 remarkedly retarded tumor growth in immune-excluded and immune-desert models, with superior antitumor activity to monotherapies. Flow cytometry, bulk RNA-seq, and scRNA-seq assays indicated that the combination therapy simultaneously boosted the innate and adaptive immunity, promoted antigen presentation, improved T cell migration and chemotaxis, and upregulated the numbers and activities of tumor-infiltrating lymphocytes. Our results demonstrate that MSA-2 synergizes with YM101 in boosting antitumor immunity. This immune cocktail therapy effectively overcomes immunotherapy resistance in immune-excluded and immune-desert models.