Radiation-induced lung fibrosis (RILF) is a severe side effect of radiotherapy in lung cancer patients that presents as a progressive pulmonary injury combined with chronic inflammation and exaggerated organ repair. RILF is a major barrier to improving the cure rate and well-being of lung cancer patients because it limits the radiation dose that is required to effectively kill tumor cells and diminishes normal lung function. Although the exact mechanism is unclear, accumulating evidence suggests that various cells, cytokines and regulatory molecules are involved in the tissue reorganization and immune response modulation that occur in RILF. In this review, we will summarize the general symptoms, diagnostics, and current understanding of the cells and molecular factors that are linked to the signaling networks implicated in RILF. Potential approaches for the treatment of RILF will also be discussed. Elucidating the key molecular mediators that initiate and control the extent of RILF in response to therapeutic radiation may reveal additional targets for RILF treatment to significantly improve the efficacy of radiotherapy for lung cancer patients.

The tumor adaptive resistance to therapeutic radiation remains to be a barrier for further improvement of local cancer control. SIRT3, a member of the sirtuin family of NAD+-dependent protein deacetylases in mitochondria, promotes metabolic homeostasis through regulation of mitochondrial protein deacetylation and plays a key role in prevention of cell aging. Here, we demonstrate that SIRT3 expression is induced in an array of radiation-treated human tumor cells and their corresponding xenograft tumors including colon cancer HCT-116, glioblastoma U87 and breast cancer MDA-MB231 cells. The SIRT3 transcriptional activation is due to SIRT3 promoter activation controlled by the stress transcription factor NF-κB. Post-transcriptionally, the SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by Cyclin B1/CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3. Cells expressing the Thr150Ala/Ser159Ala mutant SIRT3 show a reduction in the mitochondrial protein lysine deacetylation, ΔΨm, MnSOD activity and mitochondrial ATP generation. The clonogenicity of Thr150Ala/Ser159Ala mutant transfectants is lower and significantly decreased under radiation. Tumors harboring the Thr150Ala/Ser159Ala mutant SIRT3 show inhibited growth and sensitivity to in vivo local irradiation. These results demonstrate that enhanced SIRT3 transcription and post-translational modifications in mitochondria contribute to the adaptive radioresistance in tumor cells. The CDK1-mediated SIRT3 phosphorylation is a potential effective target to sensitize tumor cells to radiotherapy.

Although the efficacy of cancer radiotherapy (RT) can be enhanced by targeted immunotherapy, the immunosuppressive factors induced by radiation on tumor cells remain to be identified. Here, we report that CD47-mediated anti-phagocytosis is concurrently upregulated with HER2 in radioresistant breast cancer (BC) cells and RT-treated mouse syngeneic BC. Co-expression of both receptors is more frequently detected in recurrent BC patients with poor prognosis. CD47 is upregulated preferentially in HER2-expressing cells, and blocking CD47 or HER2 reduces both receptors with diminished clonogenicity and augmented phagocytosis. CRISPR-mediated CD47 and HER2 dual knockouts not only inhibit clonogenicity but also enhance macrophage-mediated attack. Dual antibody of both receptors synergizes with RT in control of syngeneic mouse breast tumor. These results provide the evidence that aggressive behavior of radioresistant BC is caused by CD47-mediated anti-phagocytosis conjugated with HER2-prompted proliferation. Dual blockade of CD47 and HER2 is suggested to eliminate resistant cancer cells in BC radiotherapy.

Emerging pathogenic viruses such as Ebola and Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) can cause acute infections through the evasion of the host's antiviral immune responses and by inducing the upregulation of inflammatory cytokines. This immune dysregulation, termed a cytokine storm or hypercytokinemia, is potentially fatal and is a significant underlying factor in increased mortality of infected patients. The prevalence of global outbreaks in recent years has offered opportunities to study the progression of various viral infections and have provided an improved understanding of hypercytokinemia associated with these diseases. However, despite this increased knowledge and the study of the infections caused by a range of emerging viruses, the therapeutic options still remain limited. This review aims to explore alternative experimental strategies for treating hypercytokinemia induced by the Ebola, avian influenza and Dengue viruses; outlining their modes of action, summarizing their preclinical assessments and potential clinical applications.

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