Multiple myeloma (MM) is a clonal B cell malignancy characterized by an excess of mature plasma cells in the bone marrow. MM progression is enabled by tumor cells interacting within the bone marrow with different cell types that directly promote tumor cell proliferation and survival and contribute to a progressive impairment of anti-tumor immune response. Natural Killer (NK) cells represent a subset of innate lymphoid cells that play a key role in the immunosurveillance of MM. Relevant NK cell alterations resulting in poor disease control have been reported in MM patients. In the last years, a better understanding of MM biology and its role in immune dysregulation has led to an increasing interest in the clinical potential of immunotherapy for the treatment of this disease. Accumulating evidence suggests that type I interferon (IFN) production within the tumor microenvironment is important in shaping the anti tumor-immune response including the promotion of NK cell-mediated effector functions. In this regard, cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon genes (STING) pathway that leads to type I interferon production has recently emerged as nodal player in cancer immunity and is currently being explored as potential therapeutic target. The main objective of our proposal relies on the activation of cGAS/STING pathway either in cancer and in bone marrow stromal cells by using different approaches including the usage of cyclic nucleotides, the synthesis on new lipid nanoparticles carrying cGAMP and the treatment with therapeutic DNA damaging agents. Moreover, the development of new models aimed at culturing primary myeloma, NK cells and bone marrow stromal cells in a three-dimensional (3D) environment will be pursued. We envisage that these experiments will provide the rationale for the combined use of cGAMP nanoparticles, checkpoint inhibitor drugs or therapeutic drugs for cancer treatment in order to overcome tumor immune evasion.
