With the success of immune checkpoint inhibitors (ICIs), significant progress has been made in the field of cancer immunotherapy. Despite the long-lasting outcomes in responders, the majority of patients with cancer still do not benefit from this revolutionary therapy. Increasing evidence suggests that one of the major barriers limiting the efficacy of immunotherapy seems to coalesce with the hypoxic tumor microenvironment (TME), which is an intrinsic property of all solid tumors. In addition to its impact on shaping tumor invasion and metastasis, the hypoxic TME plays an essential role in inducing immune suppression and resistance though fostering diverse changes in stromal cell biology. Therefore, targeting hypoxia may provide a means to enhance the efficacy of immunotherapy. In this review, the potential impact of hypoxia within the TME, in terms of key immune cell populations, and the contribution to immune suppression are discussed. In addition, we outline how hypoxia can be manipulated to tailor the immune response and provide a promising combinational therapeutic strategy to improve immunotherapy.

Radiotherapy (RT) is a major treatment for malignant tumors. The latest data show that >70% of patients with malignant tumors need RT at different periods. Skin changes can be experienced by up to 95% of patients who underwent RT. Inflammation and oxidative stress (OS) have been shown to be generally associated with radiation-induced skin reactions (RISRs). Inflammatory response and OS interact and promote each other during RISRs. Severe skin reactions often have a great impact on the progress of RT. The treatment of RISRs is particularly critical because advanced RT technology can also lead to skin reactions. RISRs are classified into acute and chronic reactions. The treatment methods for acute RISRs include steroid treatment, creams, ointments, and hydrocolloid dressings, depending on the reaction grading. Chronic RISRs includes chronic ulcerations, telangiectasias, and fibrosis of the skin, and advanced ­treatments such as mesenchymal stem cells, hyperbaric oxygen therapy, superoxide dismutase, and low-intensity laser therapy can be considered. Here, we review and summarize the ­important mechanisms that cause RISRs as well as the standard and advanced treatments for RISRs.

Radiotherapy (RT) is currently one of the leading treatments for various cancers; however, it may cause damage to healthy tissue, with both short-term and long-term side effects. Severe radiation-induced normal tissue damage (RINTD) frequently has a significant influence on the progress of RT and the survival and prognosis of patients. The redox system has been shown to play an important role in the early and late effects of RINTD. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the main sources of RINTD. The free radicals produced by irradiation can upregulate several enzymes including nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), lipoxygenases (LOXs), nitric oxide synthase (NOS), and cyclooxygenases (COXs). These enzymes are expressed in distinct ways in various cells, tissues, and organs and participate in the RINTD process through different regulatory mechanisms. In recent years, several studies have demonstrated that epigenetic modulators play an important role in the RINTD process. Epigenetic modifications primarily contain noncoding RNA regulation, histone modifications, and DNA methylation. In this article, we will review the role of oxidative stress and epigenetic mechanisms in radiation damage, and explore possible prophylactic and therapeutic strategies for RINTD.

Radiation-induced fibrosis (RIF) is a severe long-term complication of the normal tissue following radiotherapy. Its prototypical characteristic is the persistent activation of myofibroblasts, resulting in proportion disorder and hyperplasia remodeling of the extracellular matrix comprising collagen. The continuous progress of RIF may contribute to multiple clinical manifestations such as hollow organ stenosis, impaired gaseous diffusion, and loss of tissue compliance significantly affecting the overall quality of daily life in patients with irradiated cancer. Traditionally, the potential mechanism of myofibroblast activation and differentiation has not been elucidated, and the process has been considered as static and irreversible. Recent studies have shown that RIF is a dynamic, multi-step process mediated by many regulated chemokines and cytokines. The RIF process includes release of reactive oxygen species (ROS), microvascular injury, recruitment of inflammatory cells, and activation of myofibroblasts. Numerous signaling pathways are involved in the initiation and progression of RIF, of which SMAD-regulated CTGF expression mediated by TGF-β1 is referred as the main axis. Current management strategies applied in clinical practice for patients with RIF are only supportive treatments, such as anti-inflammatory therapy using steroids; however, the efficacies achieved by these interventions are limited and unsatisfactory. Therefore, this review explores advances in RIF pathogenesis and anti-fibrosis therapy. We hope to provide clinicians with improved awareness and enormous promise in the management of RIF.

Radiotherapy (RT) is currently one of the leading treatment for various cancers and it may cause injury to healthy tissue, with both short-term and long-term side effects. Inflammatory responses play an important role in the adverse reactions of early and late ionizing radiation. Nucleotide-binding domain and leucine-rich-repeat-containing family pyrin 3 (NLRP3) inflammasome as a multi-protein complex that activates caspase-1 can give rise to the proinflammatory cytokines such as interleukin-18 (IL-18) and interleukin-1 beta (IL-1β) maturation. Recent experiments and studies have shown that up-regulation of NLRP3 inflammasome have a big impact on radiation damage, which include radiation-induced oral mucositis, radiation-induced skin reactions, radiation-induced lung damage, radiation-induced intestinal injury and radiation-induced changes in other systems. In this paper, we will review the role of NLRP3 inflammasome in radiation damage, to explore possible therapeutic strategies for radiation damage.

Radiation‐induced myocardial fibrosis (RIMF) is a potentially lethal clinical complication of chest radiotherapy (RT) and a final stage of radiation‐induced heart disease (RIHD). RIMF is characterized by decreased ventricular elasticity and distensibility, which can result in decreased ejection fraction, heart failure and even sudden cardiac death. Together, these conditions impair the long‐term health of post‐RT survivors and limit the dose and intensity of RT required to effectively kill tumour cells. Although the exact mechanisms involving in RIMF are unclear, increasing evidence indicates that the occurrence of RIMF is related to various cells, regulatory molecules and cytokines. However, accurately diagnosing and identifying patients who may progress to RIMF has been challenging. Despite the urgent need for an effective treatment, there is currently no medical therapy for RIMF approved for routine clinical application. In this review, we investigated the underlying pathophysiology involved in the initiation and progression of RIMF before outlining potential preventative and therapeutic strategies to counter this toxicity.