Immune checkpoints are vital molecules and pathways of the immune system with defined roles of controlling immune responses from being destructive to the healthy cells in the body. They include inhibitory receptors and ligands which keep in check the recognition of most of the cancers by the immune system. This happens when proteins on the surface of T cells called immune checkpoint proteins identify partner proteins on the cancer cells and bind to them sending brake signals to the T cells to evade immune attack. However, drugs called immune checkpoint inhibitors block checkpoint proteins from binding to their partner proteins thereby inhibiting the brake signals from being sent to T cells. This eventually allows the T cells to destroy cancer cells and arbitrate robust tumor regression. Many such inhibitors have already been approved and many are in various developmental stages. The well-illustrated inhibitory checkpoints include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Though many molecules blocking these checkpoints have shown promise in the treatment of many malignancies, there is yet limited success of such treatment options in terms of the immune response in majority of the patients. In this backdrop, exploration of new pathways and next-generation inhibitors becomes imperative for development of more responsive and effective immune checkpoint therapy. Owing to the complex biology and unexplored ambiguities in the mechanistic aspects of immune checkpoint pathways, analysis of the activity profile of new drugs is the subject of strenuous investigation. We herein report the recent progress in the development of new inhibitory pathways, potential therapeutics and delineate the developments based on their merit. Further, the ensuing challenges towards the development of efficacious checkpoint therapies and the impending opportunities are also discussed.
