TNF and neoplasm: Spontaneously, these antitumor effector cells are first activated by the tumor cell-expressing surface molecules, such as calreticulin, tumor antigens in context of MHC class I molecules, and/or NKG2D ligands; then they lead apoptosis or inhibition on proliferation and angiogenesis to destroy the tumor tissue, mainly via increasing the cytotoxic factors within TME (including perforin, granzymes, IFN-α/β/γ, IL-1, IL-12, and TNF-α) (57).