Low-dose radiation therapy mobilizes antitumor immunity: New findings and future perspectives.

Radiotherapy has unique immunostimulatory and immunosuppressive effects. Although high-dose radiotherapy has been found to have systemic antitumor effects, clinically significant abscopal effects were uncommon on the basis of irradiating single lesion. Low-dose radiation therapy (LDRT) emerges as a novel approach to enhance the antitumor immune response due to its role as a leverage to reshape the tumor immune microenvironment (TIME). In this article, from bench to bedside, we reviewed the possible immunomodulatory role of LDRT on TIME and systemic tumor immune environment, and outlined preclinical evidence and clinical application. We also discussed the current challenges when LDRT is used as a combination therapy, including the optimal dose, fraction, frequency, and combination of drugs. The advantage of low toxicity makes LDRT potential to be applied in multiple lesions to amplify antitumor immune response in polymetastatic disease, and its intersection with other disciplines might also make it a direction for radiotherapy-combined modalities.

Targeted therapy for rare lung cancers: Status, challenges, and prospects.

Lung cancer causes the most cancer-related deaths worldwide. In recent years, molecular and immunohistochemical techniques have rapidly developed, further inaugurating an era of personalized medicine for lung cancer. The rare subset of lung cancers accounts for approximately 10%, each displaying distinct clinical characteristics. Treatments for rare lung cancers are mainly based on evidence from common counterparts, which may lead to unsolid clinical benefits considering intertumoral heterogeneity. The increasing knowledge of molecular profiling of rare lung cancers has made targeting genetic alterations and immune checkpoints a powerful strategy. Additionally, cellular therapy has emerged as a promising way to target tumor cells. In this review, we first discuss the current status of targeted therapy and preclinical models for rare lung cancers, as well as provide mutational profiles by integrating the results of existing cohorts. Finally, we point out the challenges and future directions for developing targeted agents for rare lung cancer.

Cu-Catalyzed Polychloromethylamination of Styrenes through C(sp3 )-H Bond Cleavage.

A copper-catalyzed three-component coupling reaction has been developed allowing the rapid building of valuable complex highly functionalized ß-polychloromethyl amines from simple styrenes, arylamines, and dichloromethane/chloroform. Using aryldiazonium salts as a radical initiator, a series of corresponding products are obtained with moderate to good yields under a carbon dioxide or nitrogen atmosphere (50 psi). In addition, good functional group tolerance can be observed.

Development and validation of a nomogram for assessing survival in extensive-stage small-cell lung cancer patients with superior vena cava syndrome referred for thoracic radiotherapy: a comparison of upfront vs. consolidative approaches.

PURPOSE: This study sought to design and validate a nomogram capable of predicting outcomes in extensive-stage small-cell lung cancer (ES-SCLC) patients with superior vena cava syndrome (SVCS) based upon the timing of their radiotherapy treatment. METHODS: We retrospectively analyzed data from 175 ES-SCLC patients with SCVS, comparing outcomes between those that underwent upfront thoracic radiotherapy (initial radiotherapy with simultaneous chemotherapy) and those that underwent consolidative thoracic radiotherapy (following 4-6 cycles of chemotherapy). Significant predictors of patient outcomes were identified using a Cox proportional hazard model and were used to construct our nomogram. This model was subsequently validated using receiver operating characteristic (ROC) curves, concordance index (C-index) values, and a risk classification system in order to evaluate its discriminative and predictive accuracy. RESULTS: The overall survival (OS) of ES-SCLC patients with SVCS that underwent chemotherapy (CT), consolidative thoracic radiotherapy (cc-TRT), and upfront thoracic radiotherapy (cu-TRT) was 8.2, 11.7, and 14.9 months, respectively (p < 0.001), with respective progression-free survival (PFS) durations of 3.3, 5.0, and 7.3 months (p < 0.001). A multivariate regression analysis revealed age, gender, ECOG performance status, sites of tumor metastasis, and treatment approach to all be independent predictors of survival outcomes. A nomogram was therefore developed incorporating these factors. C­index values upon internal and external validation of this nomogram were 0.7625 and 0.7959, respectively, and ROC and calibration curves revealed this model to be accurate and consistent. CONCLUSIONS: We found that upfront thoracic radiotherapy in combination with chemotherapy may be associated with a positive impact on outcomes in ES-SCLC patients with SVCS.

lncRNA MIR4435-2HG promoted clear cell renal cell carcinoma malignant progression via miR-513a-5p/KLF6 axis.

Long non-coding RNAs (lncRNAs) take various biological effects in clear cell renal cell carcinoma (ccRCC) mostly through sponging with microRNAs (miRNAs). lncRNA MIR4435-2HG is found to promote tumour progression in gastric cancer, glioblastoma and hepatocellular carcinoma. However, the role of lncRNA MIR4435-2HG in ccRCC progression remains unknown. The purpose of this research was to investigate the potential molecular mechanism of lncRNA MIR4435-2HG regarding the regulation of ccRCC initiation and progression. In this study, we found the up-regulation of MIR4435-2HG in ccRCC tissues and cell lines. Functionally, overexpression of MIR4435-2HG promoted the proliferation as well as the metastasis in ccRCC cell lines, whereas knockdown of MIR4435-2HG inhibited the above changes. Then, bioinformatic analysis and luciferase reporter assays confirmed the negative regulation effect of MIR4435-2HG on miR-513a-5p. And further investigations showed that KLF6, which collected from the intersection of databases, was the potential conjugated mRNAs of miR-513a-5p. Finally, the rescue experiments revealed the relation among MIR4435-2HG and KLF6, which showed that KLF6 could reverse the promoting effect of MIR4435-2HG on ccRCC in vitro and in vivo. Therefore, our findings provided insight into the mechanisms of MIR4435-2HG in ccRCC and revealed an alternative target for the clinical diagnosis and treatment of ccRCC.

Acute severe radiation pneumonitis among non-small cell lung cancer (NSCLC) patients with moderate pulmonary dysfunction receiving definitive concurrent chemoradiotherapy: Impact of pre-treatment pulmonary function parameters.

PURPOSE: Severe acute radiation pneumonitis (SARP) is a life-threatening complication of thoracic radiotherapy. Pre-treatment pulmonary function (PF) may influence its incidence. We have previously reported on the incidence of SARP among patients with moderate pulmonary dysfunction who received definitive concurrent chemoradiotherapy (dCCRT) for non-small cell lung cancer (NSCLC). METHODS: The clinical outcomes, dose-volume histograms (DVH), and PF parameters of 122 patients (forced expiratory volume in 1 s [FEV1%]: 60-69%) receiving dCCRT between 2013 and 2019 were recorded. SARP was defined as grade ≥3 RP occurring during or within 3 months after CCRT. Logistic regression, receiver operating characteristics curves (ROC), and hazard ratio (HR) analyses were performed to evaluate the predictive value of each factor for SARP. RESULTS: Univariate and multivariate analysis indicated that the ratio of carbon monoxide diffusing capacity (DLCO%; odds ratio [OR]: 0.934, 95% confidence interval [CI] 0.896-0.974, p = 0.001) and mean lung dose (MLD; OR: 1.002, 95% CI 1.001-1.003, p = 0.002) were independent predictors of SARP. The ROC AUC of combined DLCO%/MLD was 0.775 (95% confidence interval [CI]: 0.688-0.861, p = 0.001), with a sensitivity and specificity of 0.871 and 0.637, respectively; this was superior to DLCO% (0.656) or MLD (0.667) alone. Compared to the MLD-low/DLCO%-high group, the MLD-high/DLCO%-low group had the highest risk for SARP, with an HR of 9.346 (95% CI: 2.133-40.941, p = 0.003). CONCLUSION: The DLCO% and MLD may predict the risk for SARP among patients with pre-treatment moderate pulmonary dysfunction who receive dCCRT for NSCLC. Prospective studies are needed to validate our findings.

Novel use for old drugs: The emerging role of artemisinin and its derivatives in fibrosis.

Artemisinin and its derivatives are a family of anti-malarial drugs with known clinical safety and efficacy. Apart from its anti-malarial effect, artemisinin has also been reported to show anti-cancer, anti-viral, anti-parasitosis, anti-inflammatory properties in vitro and in vivo. An increasing number of studies report that artemisinin can impact the fibrotic process through various ways, such as TGF-ß, MAPK, Wnt/ß-catenin, PI3K/AKT/mTRO, FRX and Notch signaling pathways, as well as regulation of BMP-7 and cell autophagy. Moreover, the anti-inflammatory properties of artemisinin also contribute to the anti-fibrotic process. The present review summarizes the related studies on artemisinin treatment in fibrosis and elucidates the underlying mechanisms. We believe that this review can explain the potential anti-fibrotic value of artemisinin, outlining its potential use in the development of a safe and effective therapeutic method to alleviate fibrosis in the future.

Integration of stereotactic radiosurgery or whole brain radiation therapy with immunotherapy for treatment of brain metastases.

The prognosis of brain metastases (BM) is traditionally poor. BM are mainly treated by local radiotherapy, including stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT). Recently, immunotherapy (i.e., immune checkpoint inhibitors, ICI) has demonstrated a survival advantage in multiple malignancies commonly associated with BM. Individually, radiotherapy and ICI both treat BM efficiently; hence, their combination seems logical. In this review, we summarize the existing preclinical and clinical evidence that supports the applicability of radiotherapy as a sensitizer of ICI for BM. Further, we discuss the optimal timing at which radiotherapy and ICI should be administered and review the safety of the combination therapy. Data from a few clinical studies suggest that combining SRS or WBRT with ICI simultaneously rather than consecutively potentially enhances brain abscopal-like responses and survival. However, there is a lack of conclusion about the definition of "simultaneous"; the cumulative toxic effect of the combined therapies also requires further study. Thus, ongoing and planned prospective trials are needed to further explore and validate the effect, safety, and optimal timing of the combination of immunotherapy with radiotherapy for patients with BM.

Robotic-assisted partial nephrectomy with sequential clamping of segmental renal arteries for multiple ipsilateral renal tumors: initial outcomes.

BACKGROUND: To assess the technical feasibility and outcomes of robotic-assisted partial nephrectomy (RPN) with sequential segmental renal artery (SRA) clamping for multiple ipsilateral renal tumors (MIRTs). METHODS: From April 2016 to February 2018, consecutive eleven cases successfully underwent RPN with sequential SRA clamping under the guidance of dual-source computed tomography (DSCT). RESULTS: Ten cases had two lesions and two cases had three at the ipsilateral kidneys. The mean size and the mean R.E.N.A.L score for the dominant lesion of single case were 3.3 cm and 5.7, respectively. Twenty-two lesions (84.6%) had one target SRA and four (15.4%) had two target SRAs. Satisfactory ischemic areas were achieved by sequentially clamping two (81.8%) or three (18.2%) target SRAs with mean clamping time of 18.8 (15.0-27.0) min for single lesion, and the mean of total clamping time for single case was 37.5 (32.0-52.0) min. Only the complications of grade 1-2 were found and no positive surgical margin was discovered. The mean follow-up time was 5.4 months and no local recurrence or metastasis was found. The mean postoperative eGFR was 71.2 ml/minute/1.73m2 that was only an insignificant reduction (9.3%) compared with the preoperative baseline. CONCLUSION: This novel nephron-sparing technique, RPN with sequential SRA clamping, represents a good alternative for selected patients with MIRTs. With the guidance of DSCT and skilled robotic experience, this technique is feasible and can maximize renal function preservation. Large-scale multicenter clinical studies are still needed to further prove these initial outcomes.

Synergy between peroxisome proliferator-activated receptor γ agonist and radiotherapy in cancer.

Angiogenesis and inflammation are crucial processes through which the tumor microenvironment (TME) influences tumor progression. In this study, we showed that peroxisome proliferator-activated receptor γ (PPARγ) is not only expressed in CT26 and 4T1 tumor cell lines but also in cells of TME, including endothelial cells and tumor-associated macrophages (TAM). In addition, we showed that rosiglitazone may induce tumor vessel normalization and reduce TAM infiltration. Additionally, 4T1 and CT26 tumor-bearing mice treated with rosiglitazone in combination with radiotherapy showed a significant reduction in lesion size and lung metastasis. We reported that a single dose of 12 Gy irradiation strongly inhibits local tumor angiogenesis. Secretion of C-C motif chemokine ligand 2 (CCL2) in response to local irradiation facilitates the recruitment of migrating CD11b+ myeloid monocytes and TAM to irradiated sites that initiate vasculogenesis and enable tumor recurrence after radiotherapy. We found that rosiglitazone partially decreases CCL2 secretion by tumor cells and reduces the infiltration of CD11b+ myeloid monocytes and TAM to irradiated tumors, thereby delaying tumor regrowth after radiotherapy. Therefore, combination of the PPARγ agonist rosiglitazone with radiotherapy enhances the effectiveness of radiotherapy to improve local tumor control, decrease distant metastasis risks and delay tumor recurrence.

DNA repair gene polymorphisms and clinical outcome of patients with primary small cell carcinoma of the esophagus.

Polymorphisms in DNA repair genes impact on the synthesis of DNA repair proteins that are crucial to the repair of DNA damages induced by chemotherapy and radiotherapy. We retrospectively examined whether there was an association between the selected six single nucleotide polymorphisms (SNPs) of five DNA repair genes (PARP1-Val762Ala, XRCC1-Arg194Trp, XRCC1-Arg399Gln, XPC-Lys939Gln, BRCA1-Lys1183Arg, and BRCA2-Asn372His) and the clinical outcome of patients with primary small cell carcinoma of esophagus (SCCE), and it showed that the median progression-free survival (PFS) and the overall survival (OS) were 11.8 versus 9.7 months (P = 0.041) and 17.4 versus 14.8 months (P = 0.032) for patients carrying the variant allele (T/C + C/C) and the wild-type allele (T/T) of PARP1-Val762Ala polymorphism, respectively. However, no statistical significance was observed in the other five polymorphic loci (P > 0.05). When these six SNPs were combined, however, patients with at least three variant genotypes had significantly longer PFS and OS compared with those carrying less than three variant genotypes (P = 0.009 and P = 0.007, respectively). The presence of at least three polymorphic variants in certain DNA repair genes may impact on patient survival and could be a potential genomic predictor of clinical response to DNA-damaging treatment in SCCE patients.

[Simultaneous Detection of External and Internal Quality Parameters of Huping Jujube Fruits using Hyperspectral Imaging Technology].

Nondestructive detection of external and internal quality parameters of jujube is crucial for improving jujube's shelf life and industry production. Hyperspectral imaging is an emerging technique that integrates conventional imaging and spectroscopy to acquire both spatial and spectral information from a sample. It takes the advantages of the conventional RGB, near-infrared spectroscopy, and multi-spectral imaging. In this work, hyperspectral imaging technology covered the range of 450~1000 nm has been evaluated for nondestructive determination of "natural defects" (shrink, crack, insect damage and peck injury) and soluble solids content (SSC) in Huping jujube fruit. 400 RGB images were acquired through four different defect (50 for each stage) and normal (200) classes of the Huping jujube samples. After acquiring hyperspectral images of Huping jujube fruits, the spectral data were extracted from region of interests (ROIs). Using Kennard-Stone algorithm, all kinds of samples were randomly divided into training set (280) and test set (120) according to the proportion of 3:1. Seven principal components (PCs) were selected based on principal component analysis (PCA), and seven textural feature variables (contrast, correlation, energy, homogeneity, variance, mean and entropy) were extracted by gray level co-occurrence matrix (GLCM). The least squares support vector machine (LS-SVM) models were built based on the PCs spectral, textural, combined PCs and textural features, respectively. The satisfactory results show the correct discrimination rate of 92.5% for the prediction samples, as well as correlation coefficient (Rp) of 0.944 for the prediction set to calculate SSC content based on PCs and textural features. The study demonstrated that hyperspectral image technique can be a reliable tool to simultaneous detection of external ("natural defects") and internal (SSC) quality parameters of Huping jujube fruits, which provided a theoretical reference for nondestructive detection of jujube fruit.

Expression profile of apoptosis-related genes potentially explains early recurrence after definitive chemoradiation in esophageal squamous cell carcinoma.

Definitive chemoradiation is a curative treatment option for patients with locoregional esophageal squamous cell carcinoma (ESCC) who are not suitable for surgical resection, but many tend to develop local recurrence. The purpose of the study was to investigate factors affecting local recurrence of the tumor. Seventy-two patients with stage II-III thoracic ESCC who received definitive concurrent chemoradiation (CRT) and completely responded to the treatment were enrolled into this study. The case patients were 49 patients who recurred locally within 24 months after definitive CRT and 23 patients who did not have a local recurrence within 24 months were considered as controls. We investigated whether dysregulation of apoptosis-related genes was associated with early tumor recurrence. Quantitative real-time polymerase chain reaction showed upregulation of BCLAF1 and downregulation of BAG4, CARD6, IGF1R, and TNF in the tissues of case patients, as compared with controls. Among the patients with recurrent ESCC, those with tumors which exhibited more than twofold upregulated BCLAF1 and more than twofold downregulated BAG4 and TNF had a decreased time interval to local recurrence. Three gene pairs of the downregulated genes showed a significant correlation with local recurrence: BAG4 and CARD6, BAG4 and TNF, CARD6, and TNF. The patients with T3-4 disease and those with tumor >3 cm in length had a trend toward early local recurrence, though the associations were not reached statistical significance. Upregulation of BCLAF1 and downregulation of BAG4 and TNF was independently associated with early local recurrence in multivariate analysis (P < 0.05). This study supports the involvement of apoptosis-related genes in early tumor recurrence after definitive chemoradiation in patients with stage II-III thoracic ESCC.

Gene-modified mesenchymal stem cells protect against radiation-induced lung injury.

Radiation-induced lung injury (RILI) presents a common and major obstacle in the radiotherapy of thoracic cancers. The aim of this study was to examine whether RILI could be alleviated by mesenchymal stem cells (MSCs) expressing soluble transforming growth factor-ß (TGF-ß) type II receptor via an adenovirus (Ad-sTßR). Here, we systemically administered male MSCs into female mice challenged with thoracic irradiation. The data showed that either MSCs or Ad-sTßR transduced MSCs (Ad-sTßR-MSCs) specifically migrated into radiation-injured lung. Ad-sTßR-MSCs obviously alleviated lung injury, as reflected by survival and histopathology data, as well as the assays of malondialdehyde (MDA), hydroxyproline, plasma cytokines, and the expression of connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA). Furthermore, MSCs and Ad-sTßR-MSCs could adopt the characteristics of alveolar type II (ATII) cells. However, the MSCs levels in the lungs were relatively low to account for the noted therapeutic effects, suggesting the presence of other mechanisms. In vivo, MSCs-conditioned medium (MSCs CM) significantly attenuated RILI. In vitro, MSCs CM protected ATII cells against radiation-induced apoptosis and DNA damage, and modulated the inflammatory response, indicating the beneficial effects of MSCs are largely due to its paracrine activity. Our results provide a novel insight for RILI therapy that currently lack efficient treatments.

[The bio-effects of high single-dose radiation on xenografts of Lewis lung carcinoma].

OBJECTIVE: To investigate the bio-effects of high single-dose radiation on xenografts of Lewis lung carcinoma. METHODS: Female 8-week-old C57 mice bearing 4-6 mm diameter Lewis lung carcinoma tumors in the hind legs were divided into 3 groups, control group (0 Gy), high single-dose group (12 Gy/one fraction/day) and routine radiation group (22 Gy/11 fraction/15 d). The mean biological effective dose (BED) of both radiation groups was 26.4 Gy. Changes in hypoxia, DNA damage and cell cycle of the tumor cells at 1, 3, 8, 15 and 21 d after first irradiation was assessed by immunofluorescence and flow-cytometry and the tumor growth curve was also made. RESULTS: Compared to the fractionated treatment, the tumor growth was delayed after single dose irradiation. The percent of hypoxic cells after single dose radiation was lower than fractioned irradiation at 3, 8, 15 d after first radiation. The foci of gamma-H2AX showed that the single dose caused heavier DNA damages than fractioned irradiation at 1, 3 d after first radiation. The decline of G0/G1 percentage and increase of G2/M percentage of cells was found in both radiation schedules, but the G2/M percentage after single dose radiation was higher. CONCLUSION: In the C57 mice bearing Lewis lung carcinoma, the high single-dose regimen inhibits the tumor growth more than fractioned irradiation. We hypothesized that conversion of high single-dose to BED using the LQ formalism under estimated the in vivo effect of hypofractionated radiation.

[Outcomes of treatment of 32 cases of advanced or relapsed post-surgery pulmonary sarcomatoid carcinoma].

OBJECTIVE: To determine the efficacy of the third generation chemotherapy agents on relapsed post-surgery and advanced pulmonary sarcomatoid carcinoma (PSC). METHODS: We reviewed the medical records of 32 PSC patients. Their treatment modalities and survival rate, as well as risk factors associated with the survival rate including gender, age, location and size of tumor, relapse, initial diagnosis of stage, pathologic subtypes and smoking history were analysed. RESULTS: All of the 32 PSC patients received chemotherapy with gemcitabine combined with cisplatin (GP) or paclitaxel combined with cisplatin (TP). They had a median of 14 months overall survive (OS) and 5 months progress-free survive (PFS). The remission rate was 21.9%. An initial stage IV diagnosis and a larger than 6 cm tumor in diameter were independent factors associated with poor prognosis. CONCLUSION: The efficacy of TP and GP chemotherapy on patients with relapsed post-surgery and advanced PSC is comparable with that reported by other researchers. An initial stage IV diagnosis and a larger than 6 cm tumor in diameter are predictors of poor prognosis.

Challenges and opportunities in rare cancer research in China.

Cancer is one of the major public health challenges in China. Rare cancers collectively account for a considerable proportion of all malignancies. The lack of awareness of rare cancers among healthcare professionals and the general public, the typically complex and delayed diagnosis, and limited access to clinical trials are key challenges. Recent years have witnessed an increase in funding for research related to rare cancers in China. In this review, we provide a comprehensive overview of rare cancers and summarize the status of research on rare cancers in China and overseas, including the trends of funding and publications. We also highlight the challenges and perspectives regarding rare cancers in China.

Effect of testosterone replacement therapy on lower urinary tract symptoms: A systematic review and network meta-analysis.

OBJECTIVE: In this study, we aimed to perform a network meta-analysis (NMA) to investigate the effects of different testosterone replacement therapy (TRT) administration routes on lower urinary tract symptoms (LUTS) in aging men with late-onset hypogonadism (LOH). METHODS: A systematic search of PubMed, Embase, The Cochrane Library, CNKI, WanFang Data, and VIP was conducted to identify randomized controlled trials (RCTs) reporting data on International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA) level, or prostate volume. NMA was performed, and subgroup analysis was conducted to assess the impact of TRT duration on outcomes. RESULTS: A total of 21 RCTs involving 2453 participants were included. For pairwise meta-analysis, p values for TRT delivered by transdermal, intramuscular, and oral routes were as follows: IPSS: 0.93, 0.20, and 0.76; PSA level: 0.20, 0.27, and 0.98; prostate volume: 0.18, 0.04, and 0.16. There were no significant differences in IPSS, PSA level, or prostate volume between TRT routes. In subgroup analysis, long-term intramuscular TRT significantly decreased IPSS (p = 0.03), short-term transdermal TRT increased PSA levels (p < 0.001), and short-term intramuscular TRT increased the prostate volume (p = 0.04). Other forms of TRT showed no significant change in IPSS, PSA level, and prostate volume compared with the placebo. Indirect comparison of the three administration routes demonstrated no significant differences in IPSS, PSA level, and prostate volume. Nevertheless, surface under the cumulative ranking curve analysis indicated that intramuscular TRT had an 83% probability of being the best method for decreasing IPSS. CONCLUSIONS: The results demonstrate that TRT does not worsen LUTS regardless of the administration route. Intramuscular TRT may be the preferred treatment for aging men with LOH and LUTS. Intramuscular TRT may be the preferred treatment for men with LOH and LUTS. Further research is warranted to validate these findings and optimize TRT management strategies.

FLASH radiotherapy: A new milestone in the field of cancer radiotherapy.

Radiotherapy plays a pivotal role in the control and eradication of tumors, but it can also induce radiation injury to surrounding normal tissues while targeting tumor cells. In recent years, FLASH-Radiotherapy (FLASH-RT) has emerged as a cutting-edge research focus in the field of radiation therapy. By delivering high radiation doses to the treatment target in an ultra-short time, FLASH-RT produces the FLASH effect, which reduces the toxicity to normal tissues while achieving comparable tumor control efficacy to conventional radiotherapy. This review provides a brief overview of the development history of FLASH-RT and its impact on tumor control. Additionally, it focuses on introducing the protective effects and molecular mechanisms of this technology on various normal tissues, as well as exploring its synergistic effects when combined with other tumor therapies. Importantly, this review discusses the challenges faced in translating FLASH-RT into clinical practice and outlines its promising future applications.

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities.

Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.