The Immunosuppressive Tumor Microenvironment and Strategies to Revert its Immune Regulatory Milieu for Cancer Immunotherapy

In spite of the great successes in tumor immunotherapy, their therapeutic effect is not universal and scientists are far from understanding the potential obstacles that profoundly challenge their general clinical outcome. The tumor microenvironment (TME) is a fundamental aspect of cancer immunology. Based on increasing experimental and clinical evidence, it has been comprehensively accepted that the TME plays a critical role in anticancer immunity, which may result in immunotherapies and other types of therapies being ineffective. Close interaction between cancer cells and extracellular matrix and stromal cells leads to the conformation of the main construct of the TME. Within this highly heterogeneous structure, a mixture of immune and non-immune cell types is found that produce many factors driving a chronic inflammatory, immunosuppressive, and pro-angiogenic milieu. This complex tumor ecosystem paves the way for cancer cells to adapt, grow and disseminate with less possibility of being detected and eradicated by host immunosurveillance.

The previous lack of understanding of immunosuppression in cancer patients may justify the failure of several activating immunotherapeutic strategies to produce a clinical benefit. Therefore, our knowledge about the TME and the mechanisms of immune evasion by tumors and its complex network with stroma, and infiltrating immune cells could determine the success of tumor immunotherapy. Effective eradication of cancer cells by effector immune mechanisms relies on getting rid of the multiple immune-suppressive networks and activation barriers that form the TME. This aim can be achieved by targeting and reprogramming pivotal factors at the core of such networks and re-educating the TME by promoting effector T cells activity while restraining the accumulation of immunosuppressive cells. Thus, more studies on the TME composition and its impact on attenuation of immunosurveillance may provide a basis for potential strategies aimed at targeting the tumor immune microenvironment and benefit cancer patients in the future.

This Research Topic welcomes the submission of Original Research, Review, Mini Review, Opinion, and Perspective articles covering but not limited to, the following sub-topics:

• 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.

Please note: 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.