The cross talk between immune and non-immune cells in the tumor microenvironment leads to immunosuppression, which promotes tumor growth and survival. Immunotherapy is an advanced treatment that boosts humoral and cellular immunity rather than using chemotherapy or radiation-based strategy associated with non-specific targets and toxic effects on normal cells. Immune checkpoint inhibitors and T cell-based immunotherapy have already exhibited significant effects against solid tumors and leukemia. Tumor cells that escape immune surveillance create a major obstacle to acquiring an effective immune response in cancer patients. Tremendous progress had been made in recent years on a wide range of innate and adaptive immune checkpoints which play a significant role to prevent tumorigenesis, and might therefore be potential targets to suppress tumor cells growth. This review aimed to summarize the underlying molecular mechanisms of existing immunotherapy approaches including T cell and NK-derived immune checkpoint therapy, as well as other intrinsic and phagocytosis checkpoints. Together, these insights will pave the way for new innate and adaptive immunomodulatory targets for the development of highly effective new therapy in the future.