The current section of this review will focus on the mechanisms by which innate cells induce T-cell exhaustion within the TME either through direct T-cell-APC interactions (via binding of molecules such as PD-1, CTLA-4, LAG-3, Tim-3, TIGIT, B and T lymphocyte attenuator (BTLA), Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) and CD160 to the respective binding partners on tumor cells or APCs) or indirectly through cytokine/chemokine alterations (such as reduction in levels of Granzyme B, TNF-α, IFN-γ, IL-2). Here, TNF is linked to neoplasm.