In recent years, the role played by tumor-infiltrating immune cells, as a weapon to fight cancer, is gaining increasing attention and indeed, immune infiltrate characterization able to predict the outcome of immunotherapies represents a hot topic in cancer research. For instance, Immune Checkpoint Inhibitors (ICIs), targeting Cytotoxic T Lymphocyte Antigen 4 (CTLA4) or Programmed Cell Death 1 Ligand 1 (PD-L1)-Programmed Cell Death 1 (PD1) axis has impressively revolutionized the treatment landscape of many tumor types. Unfortunately, only a subset of patients benefit from these therapies aimed at unleashing anti-tumor immune response. In the majority of cancer patients, responsiveness to immunotherapy is negatively affected by the onset of immunosuppressive mechanisms, which impair T cell infiltration and cytotoxic activity and promote the accrual and activation of immunosuppressive cells, such as myeloid derived suppressor cells (MDSCs), regulatory T cells (Treg), Tumor-infiltrating macrophages (TAMs), in the tumor microenvironment (TME). There is an urgent need for clinical oncologists of new markers of tumor immune status to improve patients’ treatment allocation and to better understand trial results that are coming up.

Today’s efforts mainly focus on the dissection of the tumor microenvironment and on its genetics deregulation. Several features dictate the nature and function of immune infiltrate of TME favoring immune evasion, including oncogenic and metabolic pathways altered in tumor cells, the release of immune-related factors, miRNA, and microvesicles inducing reprogramming of immune cells towards immunosuppressive phenotype. Furthermore, new factors are emerging that can influence the immuno-evasion mechanisms of cancer cells (e.g. microbiota and its impact on the immune activation). Current knowledge of the mechanisms underlying the escape from immunosurveillance has been to date exploited to interfere with and/or disrupt these mechanisms using different approaches, but there is still room of improvement. To this aim, a deeper characterization of the complex and bidirectional cross-talk between cancer cells, immune populations and TME components is thus required to define innovative approaches to boost cancer immunosurveillance, at last maximizing the therapeutic potential of cancer immunotherapy.

The aim of this Special Issue is to provide recent findings in understanding how to boost the immune system to increase the number of immunotherapy responsive patients and to develop new unconventional approaches. We invite authors to submit original research and review articles addressing these issues.

Potential topics include but are not limited to the following:

• Discovery and characterization of new cellular and molecular mechanisms underlying resistance to immunotherapy
• Advances in cancer patients immune profiling, at tumor site and/or at systemic level
• Identification of tissue- and blood-based predictive biomarkers of immunotherapy response
• Novel approaches for reverting immunosuppression in the tumor microenvironment and favoring the efficacy of immunotherapy
• Novel immunotherapy combinations at both preclinical and clinical level