This Research Topic is the second volume of the “The Immunosuppressive Tumor Microenvironment and Strategies to Revert its Immune Regulatory Milieu for Cancer Immunotherapy” Community Series. Please see Volume I here. The field of cancer immunotherapy has witnessed significant advancements, yet the therapeutic effects remain inconsistent across different patient populations. A critical factor influencing these outcomes is the tumor microenvironment (TME), a complex and dynamic entity within cancer immunology. The TME is composed of a diverse array of immune and non-immune cells, extracellular matrix, and stromal cells, all of which contribute to a chronic inflammatory, immunosuppressive, and pro-angiogenic milieu. This environment facilitates cancer cell adaptation, growth, and dissemination, often evading host immunosurveillance. Despite the progress in understanding the TME's role in anticancer immunity, there remain substantial gaps in knowledge, particularly regarding the mechanisms of immune evasion and the intricate network between tumors, stroma, and infiltrating immune cells. Addressing these gaps is crucial for enhancing the efficacy of tumor immunotherapy and overcoming the barriers posed by the TME. This research topic aims to explore and elucidate the mechanisms by which the immunosuppressive tumor microenvironment hinders effective cancer immunotherapy. By focusing on the interactions within the TME and strategies to reprogram its immune regulatory milieu, the research seeks to identify pivotal factors that can be targeted to enhance effector T cell activity and reduce the presence of immunosuppressive cells. The ultimate goal is to develop innovative approaches that can improve the clinical outcomes of cancer immunotherapy by effectively dismantling the immune-suppressive networks within the TME. To gather further insights into the immunosuppressive tumor microenvironment and strategies to revert its immune regulatory milieu, we welcome articles addressing, but not limited to, the following themes: - Role of the immune-suppressive immune cells in TME in novel immunotherapies failure - Strategies to revert immune-suppressive activity of immune cells in TME - Immunometabolic aspects of TME immune-suppressive milieu - Experimental and clinical trials on strategies for re-educating the TME to overcome immunotherapy failure Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases, which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo), are out of scope for this section and will not be accepted as part of this Research Topic.