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Radiotherapy (RT) is delivered for purposes of local control, but can also exert systemic effect on remote and non-irradiated tumor deposits, which is called abscopal effect. The view of RT as a simple local treatment has dramatically changed in recent years, and it is now widely accepted that RT can provoke a systemic immune response which gives a strong rationale for the combination of RT and immunotherapy (iRT). Nevertheless, several points remain to be addressed such as the interaction of RT and immune system, the identification of the best schedules for combination with immunotherapy (IO), the expansion of abscopal effect and the mechanism to amplify iRT. To answer these crucial questions, we roundly summarize underlying rationale showing the whole immune landscape in RT and clinical trials to attempt to identify the best schedules of iRT. In consideration of the rarity of abscopal effect, we propose that the occurrence of abscopal effect induced by radiation can be promoted to 100% in view of molecular and genetic level. Furthermore, the “radscopal effect” which refers to using low-dose radiation to reprogram the tumor microenvironment may amplify the occurrence of abscopal effect and overcome the resistance of iRT. Taken together, RT could be regarded as a trigger of systemic antitumor immune response, and with the help of IO can be used as a radical and systemic treatment and be added into current standard regimen of patients with metastatic cancer.

Lung cancer continues to pose a serious global public health challenge. Timely evidence on the global epidemiological profile of the disease is crucial to facilitate the implementation to lung cancer control efforts. This study provides updated global estimates for lung cancer incidence and mortality in 2022, along with projections for new cases and deaths up to 2050. In the population-based study, we extracted data about lung cancer new cases and deaths from GLOBOCAN 2022 database across 185 countries or territories. We analyzed age-standardized rates by sex, country, region, and human development index (HDI). Projected new cases and deaths for 2050 were estimated using global demographic projections. In 2022, lung cancer stood as the most frequently diagnosed cancer and the primary cause of cancer-related deaths on a global scale with approximately 2.48 million new cases and 1.8 million deaths, respectively. The incidence and mortality rates of lung cancer exhibited disparities in sex and world regions. Furthermore, incidence and mortality rates increasing as HDI increased. If the incidence and mortality rates remain stable as in 2022, the burden of lung cancer is projected to increase to 4·62 million new cases and 3·55 million deaths by 2050. Lung cancer is the predominant form of cancer and the foremost contributor to cancer-related mortality in 2022 with notable geographical, sex, and socioeconomic disparities. •Lung cancer is the leading global cause of cancer incidence and mortality, with a strong link to HDI.•Significant sex disparity exists, with higher rates in males.•Urgent, customized strategies are needed to counteract the escalating lung cancer burden and health inequities worldwide.

PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors. Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial. Blocking antibodies that target PD-1 and PD-L1 have achieved remarkable response rates in cancer patients who have PD-L1-overexpressing tumors. However, using PD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the low accuracy of PD-L1 immunohistochemistry staining. Factors that affect the accuracy of PD-L1 immunohistochemistry staining are as follows. First, antibodies used in different studies have different sensitivity. Second, in different studies, the cut-off value of PD-L1 staining positivity is different. Third, PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining. Therefore, better understanding of tumor microenvironment and use of other biomarkers such as gene marker and combined index are necessary to better identify patients who will benefit from PD-1/PD-L1 checkpoint blockade therapy.

Since the successful application of messenger RNA (mRNA) vaccines in preventing COVID-19, researchers have been striving to develop mRNA vaccines for clinical use, including those exploited for anti-tumor therapy. mRNA cancer vaccines have emerged as a promising novel approach to cancer immunotherapy, offering high specificity, better efficacy, and fewer side effects compared to traditional treatments. Multiple therapeutic mRNA cancer vaccines are being evaluated in preclinical and clinical trials, with promising early-phase results. However, the development of these vaccines faces various challenges, such as tumor heterogeneity, an immunosuppressive tumor microenvironment, and practical obstacles like vaccine administration methods and evaluation systems for clinical application. To address these challenges, we highlight recent advances from preclinical studies and clinical trials that provide insight into identifying obstacles associated with mRNA cancer vaccines and discuss potential strategies to overcome them. In the future, it is crucial to approach the development of mRNA cancer vaccines with caution and diligence while promoting innovation to overcome existing barriers. A delicate balance between opportunities and challenges will help guide the progress of this promising field towards its full potential.

Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer development and immune responses, supported by mounting evidence. Cancer cells heavily rely on glutamine as a critical nutrient for survival and proliferation, while immune cells require glutamine for activation and proliferation during immune reactions. This metabolic competition creates a dynamic tug-of-war between cancer and immune cells. Targeting glutamine transporters and downstream enzymes involved in glutamine metabolism holds significant promise in enhancing anti-tumor immunity. A comprehensive understanding of the intricate molecular mechanisms underlying this interplay is crucial for developing innovative therapeutic approaches that improve anti-tumor immunity and patient outcomes. In this review, we provide a comprehensive overview of recent advances in unraveling the tug-of-war of glutamine metabolism between cancer and immune cells and explore potential applications of basic science discoveries in the clinical setting. Further investigations into the regulation of glutamine metabolism in cancer and immune cells are expected to yield valuable insights, paving the way for future therapeutic interventions.

Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1), programmed cell death ligand-1 (PD-L1), and others have shown potent clinical efficacy and have revolutionized the treatment protocols of a broad spectrum of tumor types, especially non–small-cell lung cancer (NSCLC). Despite the substantial optimism of treatment with PD-1/PD-L1 inhibitors, there is still a large proportion of patients with advanced NSCLC who are resistant to the inhibitors. Preclinical and clinical trials have demonstrated that radiotherapy can induce a systemic antitumor immune response and have a great potential to sensitize refractory “cold” tumors to immunotherapy. Stereotactic body radiation therapy (SBRT), as a novel radiotherapy modality that delivers higher doses to smaller target lesions, has shown favorable antitumor effects with significantly improved local and distant control as well as better survival benefits in various solid tumors. Notably, research has revealed that SBRT is superior to conventional radiotherapy, possibly because of its more powerful immune activation effects. Thus, PD-1/PD-L1 inhibitors combined with SBRT instead of conventional radiotherapy might be more promising to fight against NSCLC, further achieving more favorable survival outcomes. In this review, we focus on the underlying mechanisms and recent advances of SBRT combined with PD-1/PD-L1 inhibitors with an emphasis on some future challenges and directions that warrant further investigation.

PD-1/PD-L1 checkpoint blockades have achieved significant progress in several kinds of tumours. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with positive PD-L1 expression. However, PD-1/PD-L1 checkpoint blockades have not achieved breakthroughs in treating glioblastoma because glioblastoma has a low immunogenic response and an immunosuppressive microenvironment caused by the precise crosstalk between cytokines and immune cells. A phase III clinical trial, Checkmate 143, reported that nivolumab, which targets PD-1, did not demonstrate survival benefits compared with bavacizumab in recurrent glioblastoma patients. Thus, the combination of a PD-1/PD-L1 checkpoint blockade with RT, TMZ, antibodies targeting other inhibitory or stimulatory molecules, targeted therapy, and vaccines may be an appealing solution aimed at achieving optimal clinical benefit. There are many ongoing clinical trials exploring the efficacy of various approaches based on PD-1/PD-L1 checkpoint blockades in primary or recurrent glioblastoma patients. Many challenges need to be overcome, including the identification of discrepancies between different genomic subtypes in their response to PD-1/PD-L1 checkpoint blockades, the selection of PD-1/PD-L1 checkpoint blockades for primary versus recurrent glioblastoma, and the identification of the optimal combination and sequence of combination therapy. In this review, we describe the immunosuppressive molecular characteristics of the tumour microenvironment (TME), candidate biomarkers of PD-1/PD-L1 checkpoint blockades, ongoing clinical trials and challenges of PD-1/PD-L1 checkpoint blockades in glioblastoma.

Background The synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. The overlapping pulmonary toxicity induced by thoracic RT and programmed death 1/programmed death ligand-1 (PD-1/PD-L1) blockades is an important issue of clinical investigation in combination treatment. Thus far, the underlying mechanism of this toxicity remains largely unknown. Main text In this review, we discuss the unique pattern of radiation recall pneumonitis (RRP) induced by PD-1 blockade. The clinical presentation is different from common radiation pneumonitis (RP) or RRP induced by cytotoxic drugs. The immune checkpoint inhibitors may evoke an inflammatory reaction in patients’ previously irradiated fields, with infiltrating lymphocytes and potential involvement of related cytokines. All RRP patients have showed durable response to anti-PD-1/PD-L1. RRP is manageable; however, interruption of checkpoint blockades is necessary and immunosuppressive treatment should be started immediately. Further analyses of the predictive factors, including RT dosimetric parameters, tumor-infiltrating lymphocytes (TILs), and PD-L1 expression, are needed given the wide use of immune checkpoint inhibitors and high mortality from lung toxicity with the combination treatment. Conclusion Immune checkpoint inhibitors may evoke an RRP in the patients’ previously irradiated fields. Interactions between immune checkpoint inhibitors and radiotherapy should be studied further.

Radiotherapy (RT) is used routinely as a standard treatment for more than 50% of patients with malignant tumors. The abscopal effect induced by local RT, which is considered as a systemic anti-tumor immune response, reflects the regression of non-irradiated metastatic lesions at a distance from the primary site of irradiation. Since the application of immunotherapy, especially with immune checkpoint inhibitors, can enhance the systemic anti-tumor response of RT, the combination of RT and immunotherapy has drawn extensive attention by oncologists and cancer researchers. Nevertheless, the exact underlying mechanism of the abscopal effect remains unclear. In general, we speculate that the immune mechanism of RT is responsible for, or at least associated with, this effect. In this review, we discuss the anti-tumor effect of RT and immune checkpoint blockade and discuss some published studies on the abscopal effect for this type of combination therapy. In addition, we also evaluate the most appropriate time window for the combination of RT and immune checkpoint blockade, as well as the optimal dose and fractionation of RT in the context of the combined treatment. Finally, the most significant purpose of this review is to identify the potential predictors of the abscopal effect to help identify the most appropriate patients who would most likely benefit from the combination treatment modality.

Cancer remains a leading cause of death worldwide with more than 10 million new cases every year. Tumor-targeted nanomedicines have shown substantial improvements of the therapeutic index of anticancer agents, addressing the deficiencies of conventional chemotherapy, and have had a tremendous growth over past several decades. Due to the pathophysiological characteristics that almost all tumor tissues have lower pH in comparison to normal healthy tissues, among various tumor-targeted nanomaterials, pH-responsive polymeric materials have been one of the most prevalent approaches for cancer diagnosis and treatment. In this review, we summarized the types of pH-responsive polymers, describing their chemical structures and pH-response mechanisms; we illustrated the structure-property relationships of pH-responsive polymers and introduced the approaches to regulating their pH-responsive behaviors; we also highlighted the most representative applications of pH-responsive polymers in cancer imaging and therapy. This review article aims to provide general guidelines for the rational design of more effective pH-responsive nanomaterials for cancer diagnosis and treatment.