Trends in Oncology; 2021;3:1 www.omniscient.sg Review Open Access © The Author(s) 2021. www.omniscient.sg © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. New Approaches for T Cell Immunomodulation Eman Abdullah Bahattab 1 , Khalid Shah 2,3,4 , Mohannad Mokhtar Fallatah 1,2,5 * 1. National Center for Biotechnology, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia 2. KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia. 3. Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 4. Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA 5. BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA *Corresponding author: Mohannad Mokhtar Fallatah, Email: mfallatah@kacst.edu.sa Abstract Cancer is one of the leading causes of death worldwide. Despite the evolution in cancer treatment, the mortality rate is still high. The astonishing results of immune checkpoint inhibitors in patients bearing solid tumors have encouraged scientists to develop new strategies for cancer immunotherapy to further improve the clinical outcomes. Immunomodulation for cancer therapy is growing rapidly as a promising alternative approach for conventional cancer therapeutics, due to its specifcity and effcacy in suppressing growth and metastasis. However, the complexity of the tumor microenvironment and the various mechanisms whereby tumor cells escape the immune response diminishes the effcacy of many cancer immunotherapeutic drugs, especially when the drug is administered as monotherapy. Some of these factors include poor immune recognition of tumor cells, lack of suffcient drug concentration within the tumor site, and suppression of tumor-reactive T cell proliferation and effector functions. This review describes some of the novel immunomodulation strategies that have been recently developed to overcome these limitations and to augment strong antitumor immune response against different tumor types. For example, monoclonal antibodies (mAbs), CAR- T cells, Bi-specific T-cell engagers (BiTE) antibody, oncolytic viruses (OVs), cytokine-antibody fusion protein, genetically engineered mesenchymal stem cells (MSCs), oncolytic virotherapy, gut microbiota modulation and nanoparticles mediated cancer therapy. These novel strategies have been proven to augment strong antitumor immune response against different tumor types, reduced toxicity, as well as generated long-lived memory T cell population that was able to protect the host from tumor relapse. Combination therapies either with conventional or immunotherapy further improved the effcacy of cancer treatment. Keywords Immunomodulation; Checkpoint inhibitors; Co-stimulatory receptors; Bispecific antibody; Cytokine/Antibody