Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.

Breast cancer cells are characterized by heightened autophagy, which impairs tumor-associated antigen presentation and represents a significant barrier to the antitumor immunity. In this study, a PD-L1-targeting autophagy modulator (PFC@CQ) is fabricated to activate the photoimmunotherapy against breast cancer. Specifically, the hydrophobic photosensitizer protoporphyrin IX (PpIX) is covalently linked to the hydrophobic peptide FFVLK and a PD-L1-targeting peptide sequence CLQKTPKQC, resulting in the formation of an amphiphilic photosensitizer-peptide conjugate (PpIX-FFVLK-CLQKTPKQC, called PFC), which is capable of encapsulating the autophagy inhibitor chloroquine (CQ). PFC@CQ can not only facilitate the targeted drug codelivery to PD-L1-overexpressing breast cancer cells, but also effectively disrupt their immune evasion by blocking PD-1/PD-L1 pathway. Upon light irradiation, the photodynamic therapy (PDT) of PFC@CQ induces tumor cell destruction and immunogenic cell death (ICD), causing the release of damage-associated molecular patterns (DAMPs). Simultaneously, PFC@CQ can inhibit autophagy pathway to mediate the upregulation of MHC-I, thereby enhancing antigen presentation. This cascade immunomodulation promotes the dendritic cell maturation and CD8+ T cell activation, leading to a synergistic suppression of both primary and metastatic tumors. This work introduces an innovative autophagy modulation strategy with potent immunomodulatory capability, demonstrating a potential to trigger systemic antitumor immune responses through local treatment.

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms. The first key factor is innate anti-PD-1 resistance signature (IPRES), an expression of a group of genes associated with tumor plasticity and immune evasion. IPRES promotes epithelial-to-mesenchymal transition (EMT), increasing melanoma cells' invasiveness and survival. Overexpressed AXL, TWIST2, and WNT5a induce phenotypic changes. The upregulation of pro-inflammatory cytokines frequently coincides with EMT-related changes, further promoting a resistant and aggressive tumor phenotype. Inflamed tumor microenvironment may also drive the expression of resistance. The complexity of immune resistance development suggests that combination therapies are necessary to overcome it. Furthermore, targeting epigenetic regulation and exploring novel approaches such as miR-146a modulation may provide new strategies to counter resistance in melanoma.

Seasonal variations in systemic immunity have been reported. This study aimed to evaluate whether seasonality affects the efficacy of anticancer immunotherapy.

A total of 604 patients with lung cancer receiving single anti-programmed cell death (ligand) 1 (anti-PD-[L]1) inhibitors from two prospective observational cohorts were screened. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Patients were classified into two groups according to the season when the treatment started: winter (November-February) and other seasons (March-October). Kaplan-Meier analysis and Cox proportional hazards models were fitted to evaluate the impact of seasonality on survival. For validation, propensity score matching was performed.

A total of 484 patients with advanced non-small cell lung cancer were included. In an unmatched population, multivariable analysis demonstrated that the winter group (n = 173) had a significantly lower risk of progression or death from immunotherapy than the other group (n = 311) (PFS: hazard ratio [HR], 0.77 [95% confidence interval (CI), 0.62-0.96]; p = .018; OS: HR, 0.77 [95% CI, 0.1-0.98]; p = .032). In a propensity score-matched population, the winter group (n = 162) showed significantly longer median PFS (2.8 months [95% CI, 1.9-4.1 months] vs. 2.0 months [95% CI, 1.4-2.7 months]; p = .009) than the other group (n = 162). The winter group's median OS was also significantly longer than that of the other group (13.4 months [95% CI, 10.2-18.0 months] vs. 8.0 months [95% CI, 3.6-8.7 months]; p = .012). The trend toward longer survival in the winter group continued in subgroup analyses.

Starting an anti-PD-(L)1 inhibitor in winter was associated with better treatment outcomes in patients with lung cancer compared to other seasons.

The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor.

This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing.

Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group.

The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival.

The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks expression of estrogen, progesterone, and HER2 receptor targets for therapy. Polymeric nanoparticles help address the challenges in treating TNBC by enabling tailored and targeted drug delivery. Biocompatible polymeric nanoparticles leverage enhanced tumor permeability for site-specific accumulation and ligand-mediated active targeting to boost specificity. Controlled, sustained intratumorally release of encapsulated chemotherapies, such as paclitaxel and curcumin, improves antitumor efficacy as demonstrated through preclinical TNBC models. However, the practical application of these nanomedicines still has room for improvement. Advancing personalized nanoparticle platforms that align treatments to TNBC's expanding molecular subtypes shows promise. Expanding the polymer range through novel copolymers or drug conjugates may improve tumor penetration, stability, and drug encapsulation. Incorporating gene therapies, imaging agents, or triggering stimuli responsiveness into polymeric nanoparticles can also overcome innate and acquired drug resistance in TNBC while monitoring outcomes. This article reviews the different types of nanoparticles used to treat TNBC and the different mechanisms of nanoparticles that can deliver drugs to tumor cells. Collaboration across different disciplines aimed at developing combination therapies, immuno-oncology, tumor-targeting ligands, and translating preclinical safety/efficacy via scalable manufacturing practices is essential. Well-designed polymeric nanoparticles offer immense potential for patient-centric TNBC treatment, but continued optimization across bench to bedside efforts is critical for clinical realization and transforming patient outcomes.

Breast cancer (BRCA) represents a substantial global health challenge marked by inadequate early detection rates. The complex interplay between the tumor immune microenvironment and fatty acid metabolism in BRCA requires further investigation to elucidate the specific role of lipid metabolism in this disease.

We systematically integrated nine machine learning algorithms into 184 unique combinations to develop a consensus model for lipid metabolism-related prognostic genes (LMPGS). Additionally, transcriptomics analysis provided a comprehensive understanding of this prognostic signature. Using the ESTIMATE method, we evaluated immune infiltration among different risk subgroups and assessed their responsiveness to immunotherapy. Tailored treatments were screened for specific risk subgroups. Finally, we verified the expression of key genes through in vitro experiments.

We identified 259 differentially expressed genes (DEGs) related to lipid metabolism through analysis of the cancer genome atlas program (TCGA) database. Subsequently, via univariate Cox regression analysis and C-index analysis, we developed an optimal machine learning algorithm to construct a 21-gene LMPGS model. We used optimal cutoff values to divide the lipid metabolism prognostic gene scores into two groups according to high and low scores. Our study revealed distinct biological functions and mutation landscapes between high-scoring and low-scoring patients. The low-scoring group presented a greater immune score, whereas the high-scoring group presented enhanced responses to both immunotherapy and chemotherapy drugs. Single-cell analysis highlighted significant upregulation of CPNE3 in epithelial cells. Moreover, by employing molecular docking, we identified niclosamide as a potential targeted therapeutic drug. Finally, our experiments demonstrated high expression of MTMR9 and CPNE3 in BRCA and their significant correlation with prognosis.

By employing bioinformatics and diverse machine learning algorithms, we successfully identified genes associated with lipid metabolism in BRCA and uncovered potential therapeutic agents, thereby offering novel insights into the mechanisms and treatment strategies for BRCA.

The increased application of immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 in lung cancer treatment generates clinical need to reliably predict individual patients' treatment outcomes.

To bridge the prediction gap, we examine four different mathematical models in the form of ordinary differential equations, including a novel delayed response model. We rigorously evaluate their individual and combined predictive capabilities with regard to the patients' progressive disease (PD) status through equal weighting of model-derived outcome probabilities.

Fitting the complete treatment course, the novel delayed response model (R2=0.938) outperformed the simplest model (R2=0.865). The model combination was able to reliably predict patient PD outcome with an overall accuracy of 77% (sensitivity = 70%, specificity = 81%), solely through calibration with primary tumor longest diameter measurements. It autonomously identified a subset of 51% of patients where predictions with an overall accuracy of 81% (sensitivity = 81%, specificity = 81%) can be achieved. All models significantly outperformed a fully data-driven machine learning-based approach.

These modeling approaches provide a dynamic baseline framework to support clinicians in treatment decisions by identifying different treatment outcome trajectories with already clinically available measurement data.

Conjoint application of the presented approach with other predictive tools and biomarkers, as well as further disease information (e.g. metastatic stage), could further enhance treatment outcome prediction. We believe the simple model formulations allow widespread adoption of the developed models to other cancer types. Similar models can easily be formulated for other treatment modalities.

Programmed death-ligand 1 (PD-L1) has become a crucial focus in cancer immunotherapy considering it is found in many different cells. Cancer cells enhance the suppressive impact of programmed death receptor 1 (PD-1) through elevating PD-L1 expression, which allows them to escape immune detection. Although there have been significant improvements, the effectiveness of anti-PD-1/PD-L1 treatment is still limited to a specific group of patients. An important advancement in cancer immunotherapy involves improving the PD-L1 protein degradation. This review thoroughly examined the processes by which PD-L1 breaks down, including the intracellular pathways of ubiquitination-proteasome and autophagy-lysosome. In addition, the analysis revealed changes that affect PD-L1 stability, such as phosphorylation and glycosylation. The significant consequences of these procedures on cancer immunotherapy and their potential role in innovative therapeutic approaches are emphasised. Our future efforts will focus on understanding new ways in which PD-L1 degradation is controlled and developing innovative treatments, such as proteolysis-targeting chimeras designed specifically to degrade PD-L1. It is crucial to have a thorough comprehension of these pathways in order to improve cancer immunotherapy strategies and hopefully improve therapeutic effectiveness.

Immune checkpoint inhibitors (ICIs) have achieved remarkable success in clinical research and practice. Notably, liver metastasis is not sensitive to ICIs. Liver locoregional therapies can cause irreversible damage to tumor cells and release tumor antigens, thereby providing a rationale for immunotherapy treatments in liver metastasis. The combination therapy of ICIs with locoregional therapies is a promising option for patients with liver metastasis. Preclinical studies have demonstrated that combining ICIs with locoregional therapies produces a significantly synergistic anti-tumor effect. However, the current evidence for the efficacy of ICIs combined with locoregional therapies remains insufficient. Therefore, we review the literature on the mechanisms of locoregional therapies in treating liver metastasis and the clinical research progress of their combination with ICIs.

Squamous cell carcinoma of the head and neck (SCCHN) has been treated by multidisciplinary therapy consisting of surgery, radiotherapy, and cancer chemotherapy, but the recent advent of immunotherapy has produced significant changes in treatment systems and the results of these therapies. Immunotherapy has greatly improved the outcome of recurrent metastatic SCCHN, and the development of new treatment methods based on immunotherapy is now being applied not only to recurrent metastatic cases but also to locally advanced cases. To understand and practice cancer immunotherapy, it is important to understand the immune environment surrounding cancer, and the changes to which it is subject. Currently, the anti-PD-1 antibody drugs nivolumab and pembrolizumab are the only immunotherapies with proven efficacy in head and neck cancer. However, anti-PD-L1 and anti-CTLA-4 antibody drugs have also been shown to be useful in other types of cancer and are being incorporated into clinical practice. In head and neck cancer, numerous clinical trials have aimed to improve efficacy and safety by combining immunotherapy with other drug therapies and treatment modalities. Combinations of immunotherapy with cancer drugs with different mechanisms of action (cytotoxic agents, molecular-targeted agents, immune checkpoint inhibitors), as well as with radiation therapy and surgery are being investigated, and have the potential to significantly change medical care for these patients. The application of cancer immunotherapy not only to daily clinical practice but also to further therapeutic development requires a clear and complete understanding of the fundamentals of cancer immunotherapy, and knowledge of the numerous clinical studies conducted, both past and present. The results of these trials are numerous, both positive and negative, and a comprehensive understanding of this wide range of completed and ongoing clinical trials is critical to a systematic and comprehensive understanding of their scope and lessons learnt. In this article, after outlining the concepts of ``cancer immune cycle,'' ``cancer immune editing,'' and ``tumor microenvironment'' to provide an understanding of the basics of cancer immunity, we summarize the basics and clinical trial data on representative immune checkpoint inhibitors used in various cancer types, as well as recent therapeutic developments in cancer immunotherapy and the current status of these new treatments.

Edible and medicinal herbs1 (EMHs) refer to a class of substances with dual attribution of food and medicine. These substances are traditionally used as food and also listed in many international pharmacopoeias, including the European Pharmacopoeia, the United States Pharmacopoeia, and the Chinese Pharmacopoeia. Some classical formulas that are widely used in traditional Chinese medicine include a series of EMHs, which have been shown to be effective with obvious characteristics and advantages. Notably, these EMHs and Chinese classical prescriptions2 (CCPs) have also attracted attention in international herbal medicine research because of their low toxicity and high efficiency as well as the rich body of experience for their long-term clinical use.

Our purpose is to explore the potential therapeutic effect of EMHs with immune-inflammatory modulation for the study of modern cancer drugs.

In the present study, we present a detailed account of some EMHs used in CCPs that have shown considerable research potential in studies exploring modern drugs with immune-inflammatory modulation.

Approximately 500 publications in the past 30 years were collected from PubMed, Web of Science and ScienceDirect using the keywords, such as natural products, edible and medicinal herbs, Chinese medicine, classical prescription, immune-inflammatory, tumor microenvironment and some related synonyms. The active ingredients instead of herbal extracts or botanical mixtures were focused on and the research conducted over the past decade were discussed emphatically and analyzed comprehensively.

More than ten natural products derived from EMHs used in CCPs are discussed and their immune-inflammatory modulation activities, including enhancing antitumor immunity, regulating inflammatory signaling pathways, lowering the proportion of immunosuppressive cells, inhibiting the secretion of proinflammatory cytokines, immunosuppressive factors, and inflammatory mediators, are summarized.

Our findings demonstrate the immune-inflammatory modulating role of those EMHs used in CCPs and provide new ideas for cancer treatment in clinical settings.

Preserving the function and survival of pancreatic beta-cells, in order to achieve long-term glycemic control and prevent complications, is an essential feature for an innovative drug to have clinical value in the treatment of diabetes. Innovative research is developing therapeutic strategies to prevent pathogenic mechanisms and protect beta-cells from the deleterious effects of inflammation and/or chronic hyperglycemia over time. A better understanding of receptors and signaling pathways, and of how they interact with each other in beta-cells, remains crucial and is a prerequisite for any strategy to develop therapeutic tools aimed at modulating beta-cell function and/or mass. Here, we present a comprehensive review of our knowledge on membrane and intracellular receptors and signaling pathways as targets of interest to protect beta-cells from dysfunction and apoptotic death, which opens or could open the way to the development of innovative therapies for diabetes.

Inflammatory myofibroblastic tumor (IMT) is a rare pathological entity first described in 1939. This lesion is most commonly found in the lungs, but cases involving other systems, such as the central nervous system known as intracranial IMT (IIMT), have also been reported. Diagnosis currently relies on pathological results due to the lack of characteristic imaging changes. Surgical resection is an effective treatment, though the disease is invasive and may recur. Previous literature has reported a high level of programmed death 1 (PD-1) expression in IMT tissues, suggesting that immunotherapy may be effective for this condition. In this case report, we present a middle-aged male who received PD-1 inhibitor and oncolytic adenovirus (Ad-TD-nsIL12) treatment after IIMT resection surgery. This successful approach provides a new direction for the treatment of IIMT.

The prevalence of diabetes is increasing worldwide. Massive death of pancreatic beta-cells causes type 1 diabetes. Progressive loss of beta-cell function and mass characterizes type 2 diabetes. To date, none of the available antidiabetic drugs promotes the maintenance of a functional mass of endogenous beta-cells, revealing an unmet medical need. Dysfunction and apoptotic death of beta-cells occur, in particular, through the activation of intracellular protein kinases. In recent years, protein kinases have become highly studied targets of the pharmaceutical industry for drug development. A number of drugs that inhibit protein kinases have been approved for the treatment of cancers. The question of whether safe drugs that inhibit protein kinase activity can be developed and used to protect the function and survival of beta-cells in diabetes is still unresolved. This review presents arguments suggesting that several protein kinases in beta-cells may represent targets of interest for the development of drugs to treat diabetes.

The introduction of PARP inhibitors (PARPis) and immune checkpoint inhibitors (ICIs) has marked a significant shift in the treatment landscape for solid tumors. Emerging preclinical evidence and initial clinical trials have indicated that the synergistic application of PARPis and ICIs may enhance treatment efficacy and potentially improve long-term patient outcomes. Nonetheless, how to identify specific tumor types and molecular subgroups most likely to benefit from this combination remains an area of ongoing research. This review thoroughly examines current studies on the co-administration of PARPis and ICIs across various solid tumors. It explores the underlying mechanisms of action, evaluates clinical efficacy, identifies potential responder populations, and delineates common adverse events alongside strategic management approaches. The aim is to offer a detailed understanding of this combination therapy, potentially guiding future therapeutic strategies for solid tumors.

Nivolumab plus chemotherapy in the first-line setting has demonstrated clinical efficacy in patients with human epidermal growth factor receptor 2-negative advanced or metastatic gastric cancer, and is currently indicated as a standard treatment. Programmed death-ligand 1 (PD-L1) expression is an important biomarker for predicting response to anti-programmed death 1/PD-L1 agents in several solid tumors, including gastric cancer. In the CheckMate-649 trial, significant clinical improvements were observed in patients with PD-L1 combined positive score (CPS) ≥ 5, determined using the 28-8 pharmDx assay. Accordingly, an accurate interpretation of PD-L1 CPS, especially at a cutoff of 5, is important. The CPS method evaluates both immune and tumor cells and provides a comprehensive assessment of PD-L1 expression in the tumor microenvironment of gastric cancer. However, CPS evaluation has several limitations, one of which is poor interobserver concordance among pathologists. Despite these limitations, clinical indications relying on PD-L1 CPS are increasing. In response, Korean gastrointestinal pathologists held a consensus meeting for the interpretation of PD-L1 CPS in gastric cancer. Eleven pathologists reviewed 20 PD-L1 slides with a CPS cutoff close to 5, stained with the 28-8 pharmDx assay, and determined the consensus scores. The issues observed in discrepant cases were discussed. In this review, we present cases of gastric cancer with consensus PD-L1 CPS. In addition, we briefly touch upon current practices and clinical issues associated with assays used for the assessment of PD-L1 expression in gastric cancer.

The programmed death-ligand 1 (PD-L1) SP142 assay identifies patients with triple-negative breast cancer (TNBC) who are most likely to respond to the anti-PD-L1 agent atezolizumab. We aimed to compare PD-L1 (SP142) expression between primary and recurrent/metastatic TNBCs and elucidate the clinicopathological features associated with its expression.

Primary and recurrent/metastatic TNBCs tested with PD-L1 (SP142) were collected, and clinicopathological information of these cases was obtained through a review of slides and medical records.

PD-L1 (SP142) positivity was observed in 50.9% (144/283) of primary tumors and 37.8% (31/82) of recurrent/metastatic TNBCs with a significant difference. Recurrent or metastatic sites were associated with PD-L1 positivity, with high PD-L1 positivity in the lung, breast, and soft tissues, and low positivity in the bone, skin, liver, and brain. When comparing PD-L1 expression between primary and matched recurrent/metastatic TNBCs using 55 paired samples, 20 cases (36.4%) showed discordance; 10 cases revealed positive conversion, and another 10 cases revealed negative conversion during metastatic progression. In primary TNBCs, PD-L1 expression was associated with a higher histologic grade, lower T category, pushing border, and higher tumor-infiltrating lymphocyte infiltration. In survival analyses, PD-L1 positivity, especially high positivity, was found to be associated with favorable prognosis of patients.

PD-L1 (SP142) expression was lower in recurrent/metastatic TNBCs, and substantial cases showed discordance in its expression between primary and recurrent/metastatic sites, suggesting that multiple sites may need to be tested for PD-L1 (SP142) when considering atezolizumab therapy. PD-L1 (SP142)-positive TNBCs seems to be associated with favorable clinical outcomes.

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10-03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10-04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Globally, breast cancer is the second most common cause of cancer-related deaths among women. In breast cancer, microRNAs (miRNAs) are essential for both the initiation and development of tumors. It has been suggested that the tumor suppressor microRNA-561-3p (miR-561-3p) is crucial in arresting the growth of cancer cells. Further research is necessary to fully understand the role and molecular mechanism of miR-561 in human BC. The aim of this study was to investigate the inhibitory effect of miR-561-3p on ZEB1, HIF1A, and MYC expression as oncogenes that have the most impact on PD-L1 overexpression and cellular processes such as proliferation, apoptosis, and cell cycle in breast cancer (BC) cell lines. The expression of ZEB1, HIF1A, and MYC genes and miR-561-3p were measured in BC clinical samples and cell lines via qRT-PCR. The luciferase assay, MTT, Annexin-PI staining, and cell cycle experiments were used to assess the effect of miR-561-3p on candidate gene expression, proliferation, apoptosis, and cell cycle progression. Flow cytometry was used to investigate the effects of miR-561 on PD-L1 suppression in the BC cell line. The luciferase assay showed that miRNA-561-3p targets the 3'-UTRs of ZEB1, HIF1A and MYC genes significantly. In BC tissues, the qRT-PCR results demonstrated that miR-561-3p expression was downregulated and the expression of ZEB1, HIF1A and MYC genes was up-regulated. It was shown that overexpression of miR-561-3p decreased PD-L1 expression and BC cell proliferation, and induced apoptosis and cell cycle arrest through downregulation of candidate oncogenes. Furthermore, inhibition of candidate genes by miR-561-3p reduced PD-L1 at both mRNA and protein levels. Our research investigated the impact of miR-561-3p on the expression of ZEB1, HIF1A and MYC in breast cancer cells for the first time. Our findings may help clarify the role of miR-561-3p in PD-L1 regulation and point to this miR as a potential biomarker and novel therapeutic target for cancer immunotherapy.

Immunotherapy has emerged as a revolutionary approach in cancer therapy, and recent advancements hold significant promise for breast cancer (BCa) management. Employing the patient's immune system to combat BCa has become a focal point in immunotherapeutic investigations. Strategies such as immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), and targeting the tumor microenvironment (TME) have disclosed encouraging clinical outcomes. ICIs, particularly programmed cell death protein 1 (PD-1)/PD-L1 inhibitors, exhibit efficacy in specific BCa subtypes, including triple-negative BCa (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive cancers. ACT approaches, including tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy, showed promising clinical outcomes in enhancing tumor recognition and elimination. Targeting the TME through immune agonists and oncolytic viruses signifies a burgeoning field of research. While challenges persist in patient selection, resistance mechanisms, and combination therapy optimization, these novel immunotherapies hold transformative potential for BCa treatment. Continued research and clinical trials are imperative to refine and implement these innovative approaches, paving the way for improved outcomes and revolutionizing the management of BCa. This review provides a concise overview of the latest immunotherapies (2023 studies) in BCa, highlighting their potential and current status.

Pulmonary infections are a crucial health concern for patients with advanced non-small-cell lung cancer (NSCLC). Whether the clinical outcome of pulmonary infection is influenced by immunotherapy(IO) remains unclear. By evaluating immune signatures, this study investigated the post-immunotherapy risk of pulmonary infection in patients with lung cancer and identified circulating biomarkers that predict post-immunotherapy infection.

Blood specimens were prospectively collected from patients with NSCLC before and after chemotherapy(C/T) and/or IO to explore dynamic changes in immune signatures. Real-world clinical data were extracted from medical records for outcome evaluation. Mass cytometry and ELISA were employed to analyze immune signatures and cytokine profiles to reveal potential correlations between immune profiles and the risk of infection.

The retrospective cohort included 283 patients with advanced NSCLC. IO was associated with a lower risk of pneumonia (odds ratio=0.46, p=0.012). Patients receiving IO and remained pneumonia-free exhibited the most favorable survival outcomes compared with those who received C/T or developed pneumonia (p<0.001). The prospective cohort enrolled 30 patients. The proportion of circulating NK cells significantly increased after treatment in IO alone (p<0.001) and C/T+IO group (p<0.01). An increase in cell densities of circulating PD-1+CD8+(cytotoxic) T cells (p<0.01) and PD-1+CD4+ T cells (p<0.01) were observed in C/T alone group after treatment. In IO alone group, a decrease in cell densities of TIM-3+ and PD-1+ cytotoxic T cells (p<0.05), and PD-1+CD4+ T cells (p<0.01) were observed after treatment. In C/T alone and C/T+IO groups, cell densities of circulating PD-1+ cytotoxic T cells significantly increased in patients with pneumonia after treatment(p<0.05). However, in IO alone group, cell density of PD-1+ cytotoxic T cells significantly decreased in patients without pneumonia after treatment (p<0.05). TNF-α significantly increased after treatment with IO alone (p<0.05) but decreased after C/T alone (p<0.01).

Our results indicate that the incorporation of immunotherapy into treatment regimens may potentially offer protective effects against pulmonary infection. Protective effects are associated with reduction of exhausted T-cells and augmentation of TNF-α and NK cells. Exhausted T cells, NK cells, and TNF-α may play crucial roles in immune responses against infections. These observations highlight the potential utility of certain circulating biomarkers, particularly exhausted T cells, for predicting post-treatment infections.

The evolution of the complex immune system is equipped to defend against perilous intruders and concurrently negatively regulate the deleterious effect of immune-mediated inflammation caused by self and nonself antigens. Regulatory T-cells (Tregs) are specialized cells that minimize immune-mediated inflammation, but in malignancies, this feature has been exploited toward cancer progression by keeping the antitumor immune response in check. The modulation of Treg cell infiltration and their induction in the TME (tumor microenvironment) alongside associated inhibitory molecules, both soluble or membranes tethered in the TME, have proven clinically beneficial in boosting the tumoricidal activity of the immune system. Moreover, Treg-associated immune checkpoints pose a greater obstruction in cancer immunotherapy. Inhibiting or blocking active immune checkpoint signaling in combination with other therapies has proven clinically beneficial. This review summarizes the ontogeny of Treg cells and their migration, stability, and function in the TME. We also elucidate the Treg-associated checkpoint moieties that impede effective antitumor activity and harness these molecules for effective and targeted immunotherapy against cancer nuisance.

Glioblastoma is a fatal intracranial tumor with a poor prognosis, exhibiting uninterrupted malignant progression, widespread invasion throughout the brain leading to the destruction of normal brain tissue and inevitable death. Monoclonal antibodies alone or conjugated with cytotoxic payloads to treat patients with different solid tumors showed effective. This treatment strategy is being explored for patients with glioblastoma (GBM) to obtain meaningful clinical responses and offer new drug options for the treatment of this devastating disease. In this review, we summarize clinical data (from pubmed.gov database and clinicaltrial.gov database) on the efficacy and toxicity of naked antibodies and antibody-drug conjugates (ADCs) against multiple targets on GBM, elucidate the mechanisms that ADCs act at the site of GBM lesions. Finally, we discuss the potential strategies for ADC therapies currently used to treat GBM patients.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including first-line, adjuvant, and neo-adjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease, albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma.

Checkpoint inhibitors (CPIs) can trigger complications related to the autoimmune process such as CPI-triggered diabetes mellitus. The typical treatment for CPI-triggered diabetes is insulin, but a detailed therapeutic method has not yet been established. To prevent severe symptoms and mortality of diabetic ketoacidosis in advanced-stage cancer patients, the establishment of effective treatment of CPI-triggered diabetes, other than insulin therapy, is required.

We present a case of a 76-year-old man with CPI-triggered diabetes who was treated with nivolumab and ipilimumab for lung cancer. We also conducted a systematic review of 48 case reports of type 1 diabetes associated with nivolumab and ipilimumab therapy before June 2023.

The patient's hyperglycemia was not sufficiently controlled by insulin therapy, and after the remission of ketoacidosis, the addition of a sodium-glucose transporter (SGLT) 2 inhibitor, dapagliflozin, improved glycemic control. Most of the reported nivolumab/ipilimumab-induced type 1 diabetes was treatable with insulin, but very few cases required additional oral anti-diabetic agents to obtain good glucose control.

Although SGLT2 inhibitors have been reported to have adverse effects on ketoacidosis, recent studies indicate that the occurrence of ketoacidosis is relatively rare. Considering the pathological mechanism of CPI-triggered diabetes, SGLT2 inhibitors could be an effective choice if they are administered while carefully monitoring the patient's ketoacidosis.

Recent technological advancements in testing and monitoring instrumentation have greatly contributed to the progress in cancer treatment by surgical, chemotherapeutic and radiotherapeutic interventions. However, the mortality rate still remains high, calling for the development of new treatment strategies with higher efficacy. Extensive efforts driven in this direction have included broadening of early cancer screening and applying innovative theranostic nanotechnologies. They have been supported by platforms introduced to enable the detection and monitoring of cancer biomarkers, inhibitors, and other agents, able to slow down cancer progression and prevent metastasis. Despite of the well-recognized principles of the immune checkpoint blockade, the efficacy of immunotherapy achieved so far does not meet the well-founded expectations. For a successful cancer treatment, highly sensitive, robust, and inexpensive multiplex biosensors have to be designed to aid in the biomarkers monitoring and in the development of new inhibitors. In this review, we provide an overview of the efforts undertaken to aid in the development and monitoring of anticancer immunotherapy, based on the programmed cell-death immune checkpoint (PD-1/PDL-1) blockade, by designing biosensors for the detection of relevant cancer biomarkers and their inhibitors screening. This review also emphasizes alternative targets made by exosomes carrying PD-L1 overexpressed in cancer cells and passed into the excreted exosomes. Evaluated are also novel targeted drug delivery nanocarriers, providing simultaneous biosensing, thereby contributing to the emerging immune checkpoint cancer therapy. On the basis of the current trends and the emerging technologies, future perspectives of cancer diagnostics and treatment monitoring using biosensing platforms are projected.

Formulating mathematical models that estimate tumor growth under therapy is vital for improving patient-specific treatment plans. In this context, we present our recent work on simulating non-small-scale cell lung cancer (NSCLC) in a simple, deterministic setting for two different patients receiving an immunotherapeutic treatment. At its core, our model consists of a Cahn-Hilliard-based phase-field model describing the evolution of proliferative and necrotic tumor cells. These are coupled to a simplified nutrient model that drives the growth of the proliferative cells and their decay into necrotic cells. The applied immunotherapy decreases the proliferative cell concentration. Here, we model the immunotherapeutic agent concentration in the entire lung over time by an ordinary differential equation (ODE). Finally, reaction terms provide a coupling between all these equations. By assuming spherical, symmetric tumor growth and constant nutrient inflow, we simplify this full 3D cancer simulation model to a reduced 1D model. We can then resort to patient data gathered from computed tomography (CT) scans over several years to calibrate our model. Our model covers the case in which the immunotherapy is successful and limits the tumor size, as well as the case predicting a sudden relapse, leading to exponential tumor growth. Finally, we move from the reduced model back to the full 3D cancer simulation in the lung tissue. Thereby, we demonstrate the predictive benefits that a more detailed patient-specific simulation including spatial information as a possible generalization within our framework could yield in the future.

Successful clinical methods for tumor elimination include a combination of surgical resection, radiotherapy, and chemotherapy. Radiotherapy is one of the crucial components of the cancer treatment regimens which allow to extend patient life expectancy. Current cutting-edge radiotherapy research is focused on the identification of methods that should increase cancer cell sensitivity to radiation and activate anti-cancer immunity mechanisms. Radiation treatment activates various cells of the tumor microenvironment (TME) and impacts tumor growth, angiogenesis, and anti-cancer immunity. Radiotherapy was shown to regulate signaling and anti-cancer functions of various TME immune and vasculature cell components, including tumor-associated macrophages, dendritic cells, endothelial cells, cancer-associated fibroblasts (CAFs), natural killers, and other T cell subsets. Dual effects of radiation, including metastasis-promoting effects and activation of oxidative stress, have been detected, suggesting that radiotherapy triggers heterogeneous targets. In this review, we critically discuss the activation of TME and angiogenesis during radiotherapy which is used to strengthen the effects of novel immunotherapy. Intracellular, genetic, and epigenetic mechanisms of signaling and clinical manipulations of immune responses and oxidative stress by radiotherapy are accented. Current findings indicate that radiotherapy should be considered as a supporting instrument for immunotherapy to limit the cancer-promoting effects of TME. To increase cancer-free survival rates, it is recommended to combine personalized radiation therapy methods with TME-targeting drugs, including immune checkpoint inhibitors.

PD-1 and CTLA-4 can play an important role in addressing the issue of autoimmune diseases. PD-1 is a transmembrane glycoprotein expressed on T, B, and Dentric cells. This molecule functions as a checkpoint in T cell proliferation. Ligation of PD-1 with its ligands inhibits the production of IL-2, IL-7, IL-10, and IL-12 as well as other cytokines by macrophages, natural killer (NK) cells, and T cells, which can suppress cell proliferation and inflammation. Today, scientists attempt to protect against autoimmune diseases by PD-1 inhibitory signals. In this review, we discuss the structure, expression, and signaling pathway of PD-1. In addition, we discuss the importance of PD-1 in regulating several autoimmune diseases, reflecting how manipulating this molecule can be an effective method in the immunotherapy of some autoimmune diseases.

An effective systemic mechanism regulates tumor development and progression; thus, a rational design in a one-stone-two-birds strategy is meant for cancer treatment. Herein, a hollow Fe3 O4 catalytic nanozyme carrier co-loading lactate oxidase (LOD) and a clinically-used hypotensor syrosingopine (Syr) are developed and delivered for synergetic cancer treatment by augmented self-replenishing nanocatalytic reaction, integrated starvation therapy, and reactivating anti-tumor immune microenvironment. The synergetic bio-effects of this nanoplatform stemmed from the effective inhibition of lactate efflux through blocking the monocarboxylate transporters MCT1/MCT4 functions by the loaded Syr as a trigger. Sustainable production of hydrogen peroxide by catalyzation of the increasingly residual intracellular lactic acid by the co-delivered LOD and intracellular acidification enabled the augmented self-replenishing nanocatalytic reaction. Large amounts of produced reactive oxygen species (ROS) damaged mitochondria to inhibit oxidative phosphorylation as the substituted energy supply upon the hampered glycolysis pathway of tumor cells. Meanwhile, remodeling anti-tumor immune microenvironment is implemented by pH gradient reversal, promoting the release of proinflammatory cytokines, restored effector T and NK cells, increased M1-polarize tumor-associated macrophages, and restriction of regulatory T cells. Thus, the biocompatible nanozyme platform achieved the synergy of chemodynamic/immuno/starvation therapies. This proof-of-concept study represents a promising candidate nanoplatform for synergetic cancer treatment.

Triple-negative breast cancer (TNBC), although the most intractable subtype, is characterized by abundant immunogenicity, which enhances responsiveness to immunotherapeutic measures.

First, we identified CD8+ T cell core genes (TRCG) based on single-cell sequence and traditional transcriptome sequencing and then used this data to develop a first-of-its-kind classification system based on CD8+ T cells in patients with TNBC. Next, TRCG-related patterns were systematically analyzed, and their correlation with genomic features, immune activity (microenvironment associated with immune infiltration), and clinicopathological characteristics were assessed in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), the Cancer Genome Atlas (TCGA), GSE103091, GSE96058 databases. Additionally, a CD8+ T cell-related prognostic signature (TRPS) was developed to quantify a patient-specific TRCG pattern. What's more, the genes-related TRPS was validated by polymerase chain reaction (PCR) experiment.

This study, for the first time, distinguished two subsets in patients with TNBC based on the TRCG. The immune microenvironment and prognostic stratification between these have distinct heterogeneity. Furthermore, this study constructed a novel scoring system named TRPS, which we show to be a robust prognostic marker for TNBC that is related to the intensity of immune infiltration and immunotherapy. Moreover, the levels of genes related the TRPS were validated by quantitative Real-Time PCR.

Consequently, this study unraveled an association between the TRCG and the tumor microenvironment in TNBC. TRPS model represents an effective tool for survival prediction and treatment guidance in TNBC that can also help identify individual variations in TME and stratify patients who are sensitive to anticancer immunotherapy.

Despite advances in diagnostic imaging, surgical techniques, and systemic therapy, gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Unfortunately, molecular heterogeneity and, consequently, acquired resistance in GC are the major causes of failure in the development of biomarker-guided targeted therapies. However, by showing promising survival benefits in some studies, the recent emergence of immunotherapy in GC has had a significant impact on treatment-selectable procedures. Immune checkpoint inhibitors (ICIs), widely indicated in the treatment of several malignancies, target inhibitory receptors on T lymphocytes, including the programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and release effector T-cells from negative feedback signals. In this article, we review currently available predictive biomarkers (including PD-L1, microsatellite instability, Epstein-Barr virus, and tumor mutational burden) that affect the ICI treatment response, focusing on PD-L1 expression. We further briefly describe other potential biomarkers or mechanisms for predicting the response to ICIs in GC. This review may facilitate the expansion of the understanding of biomarkers for predicting the response to ICIs and help select the appropriate therapeutic approaches for patients with GC.

Neuromuscular immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) have been increasingly recognized as a consequence of expanding use of ICIs in advanced cancers. We aimed to evaluate the frequency, phenotypes, rescue treatment, and clinical outcomes of severe neuromuscular irAEs of ICIs at National Cancer Center (NCC), Korea.

Consecutive patients with newly developed severe neuromuscular irAEs (common terminology criteria for adverse events grade 3 or greater) after ICI treatment at NCC in Korea between December 2018 and April 2022 were included by searching neuromuscular diagnostic codes in electronic medical records and/or reviewing neurological consultation documentations.

Of the 1,503 ICI-treated patients, nine (0.6%) experienced severe neuromuscular irAEs; five with pembrolizumab and four with atezolizumab. The patients included five women and four men; their median age at onset was 59 years. The irAEs included Guillain-Barre syndrome (n = 5) and myasthenia gravis (MG) crisis with myositis (n = 4), and developed after a median of one (range 1-5) ICI cycle. The median modified Rankin score (mRS) was 4 (range 3-5) at the nadir. ICIs were discontinued in all patients, and rescue immunotherapy included corticosteroids (n = 9), intravenous immunoglobulin (n = 7), and plasmapheresis (n = 2). Eight patients showed improvements, with a median mRS of 3 (range 1-4); however, one patient (who had MG crisis with myocarditis) died.

In this real-world monocentric study, ICI-induced neuromuscular irAEs were rare but potentially devastating; thus, physicians should remain vigilant to enable prompt recognition and management of irAEs.

Drug repurposing opens new avenues in cancer therapy. Drug repurposing, or finding new uses for existing drugs, can substantially reduce drug discovery time and costs. Cheminformatics, genetics, and systems biology advances enable repositioning drugs. Clinical usage of PD-1/PD-L1 blocking has been approved because of its efficacy in improving prognosis in select groups. The PD-1/PD-L1 axis was considered to represent a mechanism for tumour evasion of host tumour antigen-specific T-cell immunity in early preclinical research. The expression of PD-L1 in cancer cells causes T lymphocytes to become exhausted by transmitting a co-inhibitory signal. A better understanding of how PD-L1 is regulated in cancer cells could lead to new therapeutic options. In this view, the study was aimed to repurpose the existing FDA-approved drugs as a potential PD-L1 inhibitor through e-Pharmacophore modelling, molecular docking and dynamic simulation. e-Pharmacophore screening retrieved 324 FDA-approved medications with the fitness score ≥ 1. The top 10-docked FDA candidates were compared with IN-35 (Clinical trial candidate) for its interaction pattern with critical amino acid residues. Mirabegron and Indacaterol exhibited a greater affinity for PD-L1 with docking scores of - 9.213 kcal mol-1 and - 8.023 kcal mol-1, respectively. Mirabegron retain interactions at all three major hotspots in the PD-L1 dimer interface similar to IN-35. MM-GBSA analyses indicated that Mirabegron uses less energy to create a more stable complex and retains all of the inhibitor's positive interactions found in clinical trial ligand IN-35. Molecular dynamics simulation analysis of the Mirabegron complex showed a similar pattern of deviation in correlation with IN-35, and it retains the interaction with the active key amino acids throughout the simulation time. Our present study has shown Mirabegron as a powerful inhibitor of PD-L1 expression in cancer cells using a drug-repurposing screen.

Despite human papillomavirus vaccination and screening, in about 5% of cases, cervical cancer (CC) is discovered at an initial metastatic stage. Moreover, nearly one-third of patients with locally advanced CC (LACC) will have a recurrence of their disease during follow-up. At the stage of recurrent or metastatic CC, there are very few treatment options. They are considered incurable with a very poor prognosis. For many years, the standard of care was the combination of platinum-based drug and paclitaxel with the possible addition of bevacizumab. The most recent years have seen the development of the use of immune checkpoint inhibitors (ICIs) (pembrolizumab, cemiplimab and others) in patients with CC. They have shown long term responses with improved overall survival of patients in 1st line (in addition to chemotherapy) or 2nd line (as monotherapy) treatment. Another emerging drug is tisotumab vedotin, an antibody-drug conjugate targeting tissue factor. Radiation therapy (RT) often has a limited palliative indication in metastatic cancers. However, it has been observed that RT can induce tumor shrinkage both in distant metastatic tumors beyond the radiation field and in primary irradiated tumors. This is a rarely observed phenomenon, called abscopal effect, which is thought to be related to the immune system and allows a tumor response throughout the body. It would be the activation of the immune system induced by the irradiation of cancer cells that would lead to a specific type of apoptosis, the immunogenic cell death. Today, there is a growing consensus that combining RT with ICIs may boost abscopal response or cure rates for various cancers. Here we will review the potential abscopal effect of immune-radiation therapy in metastatic cervical cancer.

Immune checkpoint inhibitors have reshaped the treatment of cancer, but they are characterized by peculiar toxicity consisting of immune-related adverse events that may potentially affect any organ or system. In this review, we summarize data on clinical presentation, diagnosis, pathogenesis, and management of the main immune-related cardiovascular toxicities of immune checkpoint inhibitors.

The most relevant immune-related cardiovascular toxicity is myocarditis, but other non-negligible reported events include non-inflammatory heart failure, conduction abnormalities, pericardial disease, and vasculitis. More recently, growing evidence suggests a role for immune checkpoint inhibitors in accelerating atherosclerosis and promoting plaque inflammation, thus leading to myocardial infarction. Immune checkpoint inhibitors are associated with several forms of cardiovascular toxicity; thus, an accurate cardiovascular baseline evaluation and periodical monitoring are required. Furthermore, the optimization of cardiovascular risk factors before, during, and after treatment may contribute to mitigating both short-term and long-term cardiovascular toxicity of these drugs.

The present study aimed to demonstrate the proportion of the programmed death-ligand 1 (PD-L1) expression in penile cancer patients and the association with clinicopathological parameters. Formalin-fixed paraffin-embedded specimens were obtained from 43 patients with primary penile squamous cell carcinoma treated at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, between 2008 and 2018. PD-L1 expression was evaluated by the immunohistochemistry using an SP263 monoclonal antibody. PD-L1 positivity was defined as >25% tumor cell staining or >25% tumor-associated immune cell staining. The correlation between PD-L1 expression and clinicopathological parameters was analyzed. A total of eight of 43 patients (18.6%) were identified as positive for PD-L1 expression in tumor cells and tumor-infiltrating lymphocytes. In the PD-L1 positive group, there was a significant association with pathological T stage (P=0.014) with a higher percentage of PD-L1 positive tumors in T1 stage compared with T2-T4 stage. In this cohort, there was a trend towards longer survival in patients with positive PD-L1 expression (5-year OS: 75% vs. 61.2%, P=0.19). Lymph node involvement and the location of tumor at the shaft of penis were two independent prognostic factors for survival. In conclusion, the PD-L1 expression was detected in 18% of penile cancer patients and high expression of PD-L1 was associated with the early T stage.

Checkpoint proteins are an integral part of the immune system and are used by the tumor cells to evade immune response, which helps them grow uncontrollably. By blocking these proteins, immune checkpoint inhibitors can restore the capability of the immune system to attack cancer cells and stop their growth. These findings are backed by adequate clinical trial data and presently, several FDA-approved immune checkpoint inhibitors exist in the market for treating various types of cancers, including melanoma, hepatocellular, endometrial, lung, kidney and others. Their mode of action is inhibition by targeting the checkpoint proteins CTLA-4, PD-1, PD-L1, etc. They can be used alone as well as in amalgamation with other cancer treatments, like surgery, radiation or chemotherapy. Since these drugs target only specific immune system proteins, their side effects are reduced in comparison with the traditional chemotherapy drugs, but may still cause a few affects like fatigue, skin rashes, and fever. In rare cases, these inhibitors are known to have caused more serious side effects, such as cardiotoxicity, and inflammation in the intestines or lungs. Herein, we provide an overview of these inhibitors and their role as biomarkers, immune-related adverse outcomes and clinical studies in the treatment of various cancers, as well as present some future perspectives.