“…Among these studies, we found of particular interest the work of: (1) Molgora and colleagues (Humanitas Clinical and Research Center, Rozzano, Italy), who demonstrated that interleukin-1 receptor 8 (IL1R8, also known as TIR8 or SIGIRR), which is known to impair the signal transduction cascades elicited by several TLRs as well as by various interleukin receptors, 116,117 negatively regulates the activity of NK cells as an immunosuppressive checkpoint; 118 (2) Lou and co-authors (Institute for Molecular Bioscience. The University of Queensland, Brisbane, Australia), who showed that SLP adaptor and CSK interacting membrane protein (SCIMP), a transmembrane adaptor protein, facilitates TLR4 signaling upon direct binding to its TIR domain;- 119 , who demonstrated that the combination of a TLR3 agonist (ARNAX), 129,130 a PD-L1-specific immune checkpoint blocker and a TAA-derived vaccine may be used to overcome resistance to PD-1-targeting therapies, at least in mice; 131 (9) Caronni and colleagues (International Centre for Genetic Engineering and Biotechnology, Trieste, Italy), who found that lactic acid blocks the ability of DCs to produce type I IFN in response to TLR3 and STING agonists 132 in a mouse model of lung cancer; 133 confirming previous reports on the major influence of local metabolism on the immune functions of the tumor microenvironment; [134][135][136][137] (10) Dooduijn and collaborators (Leiden University Medical Center Leiden, The Netherlands), who showed that TLR7/TLR8 agonism, compared to TLR3 and TLR9 agonism, drives an NK cell-dependent immune response that can eradicate tumors that have escaped immunosurveillance following MHC Class I downregulation, 138 which is in line with data from other groups demonstrating the ability of TLR7 ligands to trigger NK celldependent tumor control; 75,[139][140][141][142] (11) Klein and co-authors (University Hospital Essen, Essen, Germany), who showed that mice lacking TLR3, TLR7 and TLR9 are able to reject syngeneic wild-type malignant cells upon the activation of a tumor-targeting immune response involving both CD4 + and CD8 + T lymphocytes, suggesting that endosomal TLRs may operate as part of immunological checkpoints, at least in some settings; 143 (12) Rashedi et al (University of Toronto, Toronto, Canada), who demonstrated that mesenchymal stromal cells recruit T REG cells- 144,145 upon TLR3 or TLR4 activation, as a consequence of Notch signaling modulation…”