Effects of radiation therapy on tumor microenvironment:an updated review

Cancer is a major threat to human health and causes death worldwide.Research on the role of radiotherapy(RT)in the treatment of cancer is progressing;however,RT not only causes fatal DNA damage to tumor cells,but also affects the interactions between tumor cells and different components of the tumor microenvironment(TME),including immune cells,fibroblasts,macrophages,extracellular matrix,and some soluble products.Some cancer cells can survive radiation and have shown strong resistance to radiation through interaction with the TME.Currently,the complex relationships between the tumor cells and cellular components that play major roles in various TMEs are poorly understood.This review explores the relationship between RT and cell-cell communication in the TME from the perspective of immunity and hypoxia and aims to identify new RT biomarkers and treatment methods in lung cancer to improve the current status of unstable RT effect and provide a theoretical basis for further lung cancer RT sensitization research in the future.

Immunometabolism:a new dimension in immunotherapy resistance

Immune checkpoint inhibitors(ICIs)have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment,while substantial patients remain unresponsive or develop resistance to ICIs as a single agent,which is traceable to cellular metabolic dysfunction.Although dysregulated metabolism has long been adjudged as a hallmark of tumor,it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes.Correspondingly,people used to pay more attention to the effect of tumor cell metabolism on immunocytes,but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation,which opens up a whole new frontier called immunometabolism.The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy,whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response.Herein,we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes,and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.

IL4I1-driven AHR signature: a new avenue for cancer therapy

Aryl hydrocarbon receptor(AHR)was considered to be an important pan-tumor therapeutic target,but small molecule inhibitors targeting AHR target gene ID01 have failed in clinical trials.The recent paper published in Cell by Opitz et al.explained the failure of previous clinical trials and identified new therapeutic targets(Fig.1).

Rab22a-NeoF1:a promising target for osteosarcoma patients with lung metastasis

Osteosarcoma is the most common primary malignant bone tumor among adolescents and children,with high level of lung metastasis and poor prognosis.The treatment of metastatic cases remains a challenge in the clinic,leading to the dramatically decreased survival rate.However,the molecular mechanisms are still unclear.A recent article by Kang et al.demonstrated how chromosomal translocations in osteosarcoma facilitated lung metastasis,and shed new light on its therapeutic strategies1(Fig.1).

The cross-talk between methylation and phosphorylation in lymphoid-specific helicase drives cancer stem-like properties

Posttranslational modifications(PTMs)of proteins,including chromatin modifiers,play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties.However,the roles of Lymphoid-specific helicase(LSH),a DNA methylation modifier,in modulating stem-like properties in cancer are still not clearly clarified.Therefore,exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH.Here,we demonstrate that LSH is capable to undergo PTMs,including methylation and phosphorylation.The arginine methyltransferase PRMT5 can methylate LSH at R309 residue,meanwhile,LSH could as well be phosphorylated by MAPK1 kinase at S503 residue.We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue,which eventually promoting stem-like properties in lung cancer.Whereas,phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties,indicating the critical roles of LSH PTMs in modulating stem-like properties.Thus,our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.

Regulating tumor suppressor genes:post-translational modifications

Tumor suppressor genes cooperate with each other in tumors.Three important tumor suppressor proteins,retinoblastoma(Rb),p53,phosphatase,and tensin homolog deleted on chromosome ten(PTEN)are functionally associated and they regulated by posttranslational modification(PTMs)as well.PTMs include phosphorylation,SUMOylation,acetylation,and other novel modifications becoming growing appreciated.Because most of PTMs are reversible,normal cells use them as a switch to control the state of cells being the resting or proliferating,and PTMs also involve in cell survival and cell cycle,which may lead to abnormal proliferation and tumorigenesis.Although a lot of studies focus on the importance of each kind of PTM,further discoveries shows that tumor suppressor genes(TSGs)form a complex“network”by the interaction of modification.Recently,there are several promising strategies for TSGs for they change more frequently than carcinogenic genes in cancers.We here review the necessity,characteristics,and mechanisms of each kind of post-translational modification on Rb,p53,PTEN,and its influence on the precise and selective function.We also discuss the current antitumoral therapies of Rb,p53 and PTEN as predictive,prognostic,and therapeutic target in cancer.