It is well known that the immune microenvironment is critical to the progression of genitourinary malignancies and benign diseases. A variety of cellular and molecular properties of the immune microenvironment may influence disease outcome by altering the balance of suppressive versus inflammatory or cytotoxic responses. Emerging evidence suggests that immunoediting is a key factor of phenotypic change, immunological alterations caused by physical activity or drug treatments could promote antitumor or anti-inflammatory activity. Conversely, microenvironment deficits or dysregulation can instigate or worsen pathological progression, thereby contributing to urinary disease development and progression. Thus, understanding how immune microenvironments react and maintain appropriate antitumor or anti-inflammatory responses is important for identifying actionable therapies to improve genitourinary health. Recent technological developments, particularly in the areas of genetic modification and redox indicators, provide hopeful new treatments not only in urinary cancer, kidney cancer, bladder cancer, relatively rare adrenocortical cancer, and penile cancer but also in begin diseases like kidney stones and kidney injuries. The purpose of this topic is to provide up-to-date reviews and original articles that highlight research on immunological mediators of tumor progression and inflammatory-related genitourinary diseases, which we hope will not only integrate our current understanding but crystallize nascent questions that will help move the field forward. This research topic aims to inspire novel insights into the immunity mechanisms, novel therapeutic targets, and effective combinational strategies of urinary immunotherapies.

As we know, cancer is an important disease threatening human health. According to the latest statistics in “Global Cancer Statistics 2020”, cancer is expected to overtake cardiovascular disease as the leading cause of premature death in most countries this century. That sounds pretty terrible, but it is believed that this situation should be better along with the advances in tumor biology. There is no doubt that biomarkers have very significant clinical implications, which can be used for early diagnosis, monitoring progress, and predicting the prognosis of cancer.

Cancer immunotherapy is based on using the immune system components to fight tumors, without destroying normal cells. Several immunotherapeutic strategies have been investigated and proposed for the treatment of cancers, including cancer vaccines containing tumor antigens that are used to induce immune responses against tumors, monoclonal antibodies against tumor antigens, and immune checkpoint inhibitors. However, many clinical trials have shown that the use of these methods as monotherapy is ineffective in many cases. Many tumors can resist immunotherapy due to the absence or insufficient infiltration of tumors with CD8+ T cells and hence, are called “cold” or non-inflammatory tumors. Cold tumors are characterized by a lack of infiltrating CD8+ T cells, the presence of anti-inflammatory myeloid cells, tumor-associated M2 macrophages, and regulatory T cells. A combination of other cancer therapeutic approaches, such as chemotherapy or immunotherapy with cancer vaccines, could dramatically enhance the efficacy and, eventually, the outcome of the treatment. Despite some success of the immunotherapy of oncological diseases, cold tumors represent one of the main therapeutic challenges for modern immunotherapy. It can be expected that in the near future, treatment algorithms will be developed to adapt the therapeutic strategies to the immune context of the tumor since treatment with checkpoint inhibitors or vaccines alone is not enough for cold tumors. Therefore, using other therapeutic approaches alongside the existing treatment methods can be more reasonable for cold tumors that do not strongly stimulate the immune system or resist against it. To apply targeted treatments such as the use of small molecules, small peptides, hybrid small molecules, biologically active peptides, non-protein isolates of food products or by-products, and every material that is capable of the disturbing immunosuppressive tumor microenvironment (TME) as an adjuvant therapy can reduce the resistance of cold tumors to immunotherapy which is so-called turning them into “warm” tumors. This research topic aims to cover all outstanding advances in immunology, medical chemistry and biochemistry, pharmacology, food engineering and molecular biology of contemporary molecular drug targets involved in cancer treatment and encompasses the following subjects: • Definition and explanation of cold tumors and challenges ahead toward their treatment • Designing and application of small peptides, small molecules, and other similar materials to overcome suppressive TME and break tumors resistance • Extraction and preparation of bioactive peptides or other components derived from natural resources to make cold tumor barriers fragile • Modifications and alterations leading to overcoming cold tumor resistance against cancer vaccines and ICP inhibitors Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this topic.