HAVCR2 and neoplasm: In addition, HMGB1 binding to TIM-3 on tumor-infiltrating DCs negatively contributes to the induction of innate immunity—i.e., TIM-3-mediated signals inhibit nucleic acid-sensing TLRs, such as TLR-9, which mediates the production of proinflammatory cytokines, and thus binding of HMGB1 to TIM-3 has a negative effect on proinflammatory cytokine production [5].