Simple SummaryCancer treatment mostly involves drugs that has many side effects. In order to limit the toxicity of the chemical drugs, the scientific community embraced immunotherapy involving therapeutic antibodies targeting the tumor. In particular, immunotherapy aims to bolster the immune cells of the host (patients) to fight against cancer. Such therapies involve antibodies directed against traditional molecules in cancer and immune cells that prevent generation of autoimmunity or enable tolerance against self-antigens. This works in a subset of patients but develop resistance in others in the clinic. We suggest targeting other molecules on cancer and immune cells to overcome such resistance against immunotherapy. We discuss the possible resistance mechanisms against traditional immunotherapy and enlist new and alternative immunotherapy targets that can be employed as selective therapeutic interventions in the clinic along with low doses of chemotherapy. This will sustain and enhance the extraordinary momentum in cancer therapy.AbstractPhysiologically, well known or traditional immune checkpoints (ICs), such as CTLA-4 and PD-1, are in place to promote tolerance to self-antigens and prevent generation of autoimmunity. In cancer, the ICs are effectively engaged by the tumor cells or stromal ells from the tumor microenvironment through expression of cognate ligands for the ICs present on the cell surface of CD8+T lymphocytes. The ligation of ICs on CD8+T lymphocytes triggers inhibitory signaling pathways, leading to quiescence or an exhaustion of CD8+T lymphocytes. This results in failure of immunotherapy. To overcome this, several FDA-approved therapeutic antibodies are available, but the clinical outcome is quite variable due to the resistance encountered through upregulated expression of alternate ICs such as VISTA, LAG-3, TIGIT and TIM-3. This review focuses on the roles played by the traditional as well as alternate ICs and the contribution of associated signaling pathways in generating such resistance to immunotherapy. Combinatorial targeting of traditional and alternate ICs might be beneficial for immune-refractory tumors.