The immunosuppressive microenvironment in MM. TIGIT is frequently expressed on functionally exhausted T cells in the MM BM. At the interface between T cells and malignant PCs, the interaction between TIGIT and its ligand CD155 plays a critical role in negative regulation, including the competitive inhibition of CD226-dependent antitumor immunity. The proinflammatory MM milieu is critically implicated in the generation of immunosuppressive subsets, such as type 1 IFN–induced Tregs, versican-induced tolerogenic TAMs, and myeloid-derived suppressor cells (MDSCs) induced by S100A9 and the inflammasome-derived IL-18. Various soluble metabolites and cytokines derived from immunosuppressive subsets or malignant PCs also regulate effector lymphocyte functions. These factors include adenosine driven by ectoenzymes, indoleamine 2,3-dioxygenase (IDO)-induced tryptophan catabolites, transforming growth factor-β (TGF-β), and IL-10. ATP, adenosine triphosphate; DAMP, damage-associated molecular pattern; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; NAD, nicotinamide adenine dinucleotide; PD-1, programmed cell death protein 1; PDL-1, programmed death ligand 1; TIGIT, T-cell immunoreceptor with immunoglobulin and ITIM domains.