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.

Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1/PD-L1 to boost tumor-specific T lymphocyte immunity have opened up new avenues for the treatment of various histological types of malignancies, with the possibility of durable responses and improved survival. However, the development of acquired resistance to ICI therapy over time after an initial response remains a major obstacle in cancer therapeutics. The potential mechanisms of acquired resistance to ICI therapy are still ambiguous. In this review, we focused on the current understanding of the mechanisms of acquired resistance to ICIs, including the lack of neoantigens and effective antigen presentation, mutations of IFN‐γ/JAK signaling, and activation of alternate inhibitory immune checkpoints, immunosuppressive tumor microenvironment, epigenetic modification, and dysbiosis of the gut microbiome. Further, based on these mechanisms, potential therapeutic strategies to reverse the resistance to ICIs, which could provide clinical benefits to cancer patients, are also briefly discussed.

This article mainly observed the protective effect of sulforaphane (SFN) on radiation-induced skin injury (RISI). In addition, we will discuss the mechanism of SFN’s protection on RISI. The RISI model was established by the irradiation of the left thigh under intravenous anesthesia. Thirty-two C57/BL6 mice were randomly divided into control group (CON), SFN group, irradiation (IR) group, and IR plus SFN (IR/SFN) group. At eight weeks after irradiation, the morphological changes of mouse skin tissues were detected by H&E staining. Then, the oxidative stress and inflammatory response indexes in mouse skin tissues, as well as the expression of Nrf2 and its downstream antioxidant genes, were evaluated by ELISA, real-time PCR, and Western blotting. The H&E staining showed the hyperplasia of fibrous tissue in the mouse dermis and hypodermis of the IR group. Western blotting and ELISA results showed that the inflammasome of NLRP3, caspase-1, and IL-1β, as well as oxidative stress damage indicators ROS, 4-HNE, and 3-NT, in the skin tissues of mice in the IR group were significantly higher than those in the control group (p < 0.05). However, the above pathological changes declined sharply after SFN treatment (p < 0.05). In addition, the expressions of Nrf2 and its regulated antioxidant enzymes, including CAT and HO-1, were higher in the skin tissues of SFN and IR/SFN groups, but lower in the control and IR groups (p < 0.05). SFN may be able to suppress the oxidative stress by upregulating the expression and function of Nrf2, and subsequently inhibiting the activation of NLRP3 inflammasome and DNA damage, so as to prevent and alleviate the RISI.

Radiation therapy plays an increasingly important role in cancer treatment. It can inhibit the progression of various cancers through radiation-induced DNA breakage and reactive oxygen species (ROS) overload. Unfortunately, solid tumors, such as breast and lung cancer, often develop a hypoxic microenvironment due to insufficient blood supply and rapid tumor proliferation, thereby affecting the effectiveness of radiation therapy. Restraining hypoxia and improving the curative effect of radiotherapy have become difficult problems. Ferroptosis is a new type of cell death caused by lipid peroxidation due to iron metabolism disorders and ROS accumulation. It plays an important role in both hypoxia and radiotherapy and can enhance the radiosensitivity of hypoxic tumor cells by amplifying oxidative stress or inhibiting antioxidant regulation. In this review, we summarize the internal relationship and related mechanisms between ferroptosis and hypoxia, thus exploring the possibility of inducing ferroptosis to improve the prognosis of hypoxic tumors.

Radiation therapy is a common treatment for head and neck cancers. However, because of the presence of nerve structures (brain stem, spinal cord, and brachial plexus), salivary glands (SGs), mucous membranes, and swallowing muscles in the head and neck regions, radiotherapy inevitably causes damage to these normal tissues. Among them, SG injury is a serious adverse event, and its clinical manifestations include changes in taste, difficulty chewing and swallowing, oral infections, and dental caries. These clinical symptoms seriously reduce a patient’s quality of life. Therefore, it is important to clarify the mechanism of SG injury caused by radiotherapy. Although the mechanism of radiation-induced SG injury has not yet been determined, recent studies have shown that the mechanisms of calcium signaling, microvascular injury, cellular senescence, and apoptosis are closely related to oxidative stress. In this article, we review the mechanism by which radiotherapy causes oxidative stress and damages the SGs. In addition, we discuss effective methods to prevent and treat radiation-induced SG damage.