Programmed cell death-1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors are considered effective alternatives for the primary treatment of recurrent metastatic cancers. However, they can induce various adverse events affecting multiple organ systems, potentially diminishing patients' quality of life, and even leading to treatment interruptions. Adverse events related to PD-1/PD-L1 inhibitors differ from those associated with CTLA-4 inhibitors and are more commonly observed in the treatment of solid tumors. This study aimed to address the knowledge gap regarding adverse events related to PD-1/PD-L1 inhibitors. A visual bibliometric network was constructed using VOSviewer, CiteSpace, R software, and the Web of Science Core Collection (WoSCC) to quantitatively analyze this research field. Future research directions were also explored. The USA ranked first in publication count and total citations. Over time, publication types transitioned from case reports to clinical trials. Research on for nivolumab was the most prevalent. The spectrum of cancers treated by PD-1/PD-L1 inhibitors expanded beyond melanoma and lung cancer to include renal cell carcinoma, esophageal cancer, and others. Common adverse events included pneumonitis, myasthenia gravis, and vitiligo. There was a significant increase in multi-phase clinical trials and studies related to biomarkers. This study offers valuable insights for potential collaborators and institutions, highlighting trends in the study of adverse events related to PD-1/PD-L1 inhibitors. The management of these adverse events has become more refined and standardized. Biomarker research and multi-phase clinical trials are likely to be key areas of focus in future studies.

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.

Immune checkpoints are crucial in regulating the activation of cell-mediated and humoral immune responses. However, cancer cells hijack this mechanism to evade the immune surveillance and anti-cancer response. Typically, receptors like PD-1 and CTLA4, expressed on immune cells, prevent the activation and differentiation of T cells. They also inhibit the development of autoimmune reactions. However, ligands such as PD-L1 for the receptor PD-1 are also expressed on the surface of cancer cells that help prevent the activation of anti-cancer immune responses by blocking the signalling pathways mediated by PD-1 and CTLA4. Immune checkpoint inhibitors (ICIs) have promising therapeutic efficacy for treating several cancers by activating T cells and their differentiation into effector cells against tumours. Nonetheless, hyperactivated immune cells usually contribute to detrimental issues, also known as immune-related adverse effects (IrAE). IrAEs have been observed in multiple organs, leading to neurological issues, colitis, endocrine dysfunction, renal issues, hepatitis, pneumonitis, and dermatitis. The interplay between hyperactivated T cells and Treg cells helps in orchestrating the development of autoimmunity. Moreover, the crosstalk between proinflammatory interleukins and the development of autoantibodies also mediates the multiorgan effects of ICIs in cancer patients. IrAEs are generally managed by terminating the ICI therapy, reducing the ICI dose, and by using corticosteroids to subvert inflammation. Therefore, the present review aims to delineate the impacts of ICIs on the development of autoimmune diseases and inflammatory outcomes in cancer patients. In addition, mechanistic insight involving immune cells, cytokines, and autoantibodies for ICI-mediated IrAEs will also be discussed with updated findings in this field.

Colorectal cancer (CRC) continues to be a major worldwide health issue, with elevated death rates linked to late stages of the illness. Immunotherapy has made significant progress in developing effective techniques to improve the immune system's capacity to identify and eradicate cancerous cells. This study examines the most recent advancements in CAR-T cell treatment and exosome-based immunotherapy for CRC. CAR-T cell therapy, although effective in treating blood cancers, encounters obstacles when used against solid tumours such as CRC. These obstacles include the presence of an immunosuppressive tumour microenvironment and a scarcity of tumour-specific antigens. Nevertheless, novel strategies like dual-receptor CAR-T cells and combination therapy involving cytokines have demonstrated promise in surmounting these obstacles. Exosome-based immunotherapy is a promising approach for targeted delivery of therapeutic drugs to tumour cells, with high specificity and minimal off-target effects. However, there are still obstacles to overcome in the field, such as resistance to treatment, adverse effects associated with the immune system, and the necessity for more individualised methods. The current research is focused on enhancing these therapies, enhancing the results for patients, and ultimately incorporating these innovative immunotherapeutic approaches into the standard treatment protocols for CRC.

Invasive central nervous system (CNS) cancers are an area where the development of breakthrough therapies is urgently needed. For instance, conditions such as glioblastoma multiforme (GBM) are associated with poor clinical prognosis, with the majority of trials offering no improvement to marginally enhanced survival. Unleashing the potential of targeting the immune system in CNS cancers has gained attention in recent years. Inhibition of immune checkpoints such as CTLA-4, PD-1/PD-L1, TIM-3, and LAG-3 has been attempted in recent trials. While potentially offering a notable edge over other immunotherapies, multi-organ adverse events have been found with the administration of immune checkpoint inhibitors (ICIs). The present review captures the state-of-the-art evidence on ICI treatments in different CNS cancers. Also, we discuss the value of combinational therapies involving ICIs as well as next-generation therapeutics such as bispecific antibodies targeting PD-1/LAG-3/TIM-3 and CRISPR-Cas9-edited PD-1-knock-out checkpoint-resistant CAR T-cells.

Emerging evidence underscores gut microbiota's role in modulating lung cancer immunotherapy outcomes, though specific impacts on immune checkpoint inhibitors (ICIs) and associated adverse events (AEs) require further clarity. This review synthesizes findings from 15 studies examining gut microbiota-ICI interactions in non-small cell lung cancer (NSCLC), alongside studies investigating antibiotics, proton pump inhibitors (PPIs), probiotics, and diet as modulating factors. Results indicate that Actinobacteria, Bacteroides, and Verrucomicrobiota correlate with positive ICI responses, while Bacillota shows variable associations; notably, Bacillota-enriched patients had fewer immunotherapy-related AEs. The administration of antibiotics and PPIs within a month before ICIs was linked to diminished efficacy, whereas probiotics correlated with enhanced outcomes. Plant-based diets are also aligned with dietary patterns supportive of ICIs. These findings suggest that analyzing gut microbiota composition could improve the ability to predict NSCLC patient responses to ICIs. Additionally, judicious use of antibiotics, PPIs, probiotics, and dietary adjustments may optimize immunotherapy outcomes and mitigate adverse effects.

Immune checkpoint inhibitors, especially those targeting CD274/PD-L1yield powerful clinical therapeutic efficacy. Thoughmuch progress has been made in the development of antibody-basedCD274 drugs, chemical compounds applied for CD274degradation remain largely unavailable. Herein,baicalein, a monomer of traditional Chinese medicine, isscreened and validated to target CD274 and induces itsmacroautophagic/autophagic degradation. Moreover, we demonstrate thatCD274 directly interacts with MAP1LC3B (microtubule associatedprotein 1 light chain 3 beta). Intriguingly, baicalein potentiatesCD274-LC3 interaction to facilitate autophagic-lysosomal degradationof CD274. Importantly, targeted CD274. degradation via baicaleininhibits tumor development by boosting T-cell-mediated antitumorimmunity. Thus, we elucidate a critical role of autophagy-lysosomalpathway in mediating CD274 degradation, and conceptually demonstratethat the design of a molecular "glue" that tethers the CD274-LC3interaction is an appealing strategy to develop CD274 inhibitors incancer therapy.Abbreviations: ATTECs: autophagy-tethering compounds; AUTACs: AUtophagy-TArgeting Chimeras; AUTOTACs: AUTOphagy-TArgeting Chimeras; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; BiFC: bimolecular fluorescence complementation; BafA1: bafilomycin A1; CD274/PD-L1/B7-H1: CD274 molecule; CQ: chloroquine; CGAS: cyclic GMP-AMP synthase; DAPI: 4'6-diamino-2-phenylindole; FITC: fluorescein isothiocyanate isomer; GFP: green fluorescent protein; GZMB: granzyme B; IHC: immunohistochemistry; ICB: immune checkpoint blockade; KO: knockout; KD: equilibrium dissociation constant; LYTAC: LYsosome-TArgeting Chimera; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MST: microscale thermophoresis; NFAT: nuclear factor of activated T cells; NFKB/NF-kB: nuclear factor kappa B; NSCLC: non-small-cell lung cancer; PDCD1: programmed cell death 1; PROTACs: PROteolysis TArgeting Chimeras; PRF1: perforin 1; PE: phosphatidylethanolamine; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; STAT: signal transducer and activator of transcription; SPR: surface plasmon resonance; TILs: tumor-infiltrating lymphocyte; TME: tumor microenvironment.

The objective of this study was to identify symptom clusters in lung cancer patients receiving immunotherapy and explore their impact on the quality of life of patients.

Immunotherapy is widely used in lung cancer; however, there is little understanding of symptom clusters and their impacts on the quality of life of this population.

Cross-sectional study.

The survey contained the Memorial Symptom Assessment Scale (MSAS), Quality of Life Questionnaire-Lung Cancer 43 and a self-designed General Information Evaluation Form. Symptom clusters were identified using exploratory factor analysis (EFA) based on the symptom scores. Spearman correlation analysis was performed to evaluate the associations between each symptom cluster and the patients' quality of life. Multiple linear regression analysis was employed to examine the impact of the symptom clusters on quality of life. This study adhered to the STROBE guidelines.

In total, 240 participants completed the survey. Five symptom clusters were identified and named according to their characteristics: emotional-related symptom cluster, lung cancer-related symptom cluster, physical symptom cluster, skin symptom cluster and neural symptom cluster. All symptom clusters, except for the neural symptom cluster, had a significantly detrimental impact on patient quality of life.

Lung cancer patients undergoing immunotherapy experience a range of symptoms, which can be categorized into five clusters. These symptom clusters have a negative impact on patients' quality of life. Future research should focus on developing interventions for each symptom cluster and their influencing factors.

In the data collection phase, lung cancer patients undergoing immunotherapy were recruited to participate in the survey.

Immune checkpoint inhibitors (ICIs) have demonstrated favorable outcomes in various cancers. However, it has been observed that ICIs may induce life-threatening cardiovascular toxicity. In this study, a meta-analysis was conducted to determine the risk of cardiovascular toxicities in patients exposed to ICIs or in combination with chemotherapy. PubMed, Cochrane Library, and Embase databases were searched from inception to September 24, 2023. This study was conducted in accordance with the PRISMA guidelines. A meta-analysis was conducted on the risk of cardiotoxicity in cancer patients. Data were pooled with a random-effect model. This protocol was registered prospectively in PROSPERO (CRD42023467319). The primary outcome was cardiotoxicity risk in observational studies with ICIs or combined with chemotherapy. The risk factors that affected the occurrence of cardiovascular toxicities were also examined. ICIs or combined with chemotherapy increased the cardiotoxicity risk compared with mono-chemotherapy (OR 1.47; 95% CI 1.05-2.06, p = 0.024). The risk of pericardial disease in cardiotoxic events (OR 1.99; 95% CI 1.23-3.22, p = 0.005) and thromboembolic events (OR 1.34; 95% CI 1.04-1.72, p = 0.025) was significantly increased. Smoking (OR 1.25; 95% CI 1.12-1.39, p < 0.001), previous heart disease (OR 2.01; 95% CI 1.64-2.46, p < 0.001), and lung cancer (OR 1.46; 95% CI 1.26-1.69, p < 0.001) were risk factors worthy of attention. ICIs or combined with chemotherapy show an elevated risk of cardiovascular toxicities. Patients who are smoking, diagnosed lung cancer, and having prior medical history of heart diseases need more attention.

Among the leading methods for triggering therapeutic anti-cancer immunity is the inhibition of immune checkpoint pathways. N-glycosylation is found to be essential for the function of various immune checkpoint proteins, playing a critical role in their stability and interaction with immune cells. Removing the N-glycans of these proteins seems to be an alternative therapy, but there is a lack of a de-N-glycosylation technique for target protein specificity, which limits its clinical application. Here, we developed a novel technique for specifically removing N-glycans from a target protein on the cell surface, named deglycosylation targeting chimera (DGlyTAC), which employs a fusing protein consisting of Peptide-N-glycosidase F (PNGF) and target-specific nanobody/affibody (Nb/Af). The DGlyTAC technique was developed to target a range of glycosylated surface proteins, especially these immune checkpoints-CD24, CD47, and PD-L1, which minimally affected the overall N-glycosylation landscape and the N-glycosylation of other representative membrane proteins, ensuring high specificity and minimal off-target effects. Importantly, DGlyTAC technique was successfully applied to lead inactivation of these immune checkpoints, especially PD-L1, and showed more potential in cancer immunotherapy than inhibitors. Finally, PD-L1 targeted DGlyTAC showed therapeutic effects on several tumors in vivo, even better than PD-L1 antibody. Overall, we created a novel target-specific N-glysocylation erasing technique that establishes a modular strategy for directing membrane proteins inactivation, with broad implications on tumor immune therapeutics.

Immune checkpoint inhibitors, such as pembrolizumab, have demonstrated substantial therapeutic efficacy in the treatment of cancer. However, immune-related adverse events, including myasthenia gravis (MG), present significant clinical challenges. This study presents the case of a 75-year-old male patient who developed generalized acetylcholine receptor antibody-positive MG following the first infusion of pembrolizumab for cholangiocarcinoma. The patient's symptoms rapidly progressed to an impending myasthenic crisis (MGFA Class IVB) within 20 days of pembrolizumab administration. Eculizumab was used as a rescue therapy due to the unavailability of conventional treatments, resulting in rapid and significant symptom relief, with sustained improvement during maintenance therapy. The use of eculizumab as rescue therapy presents a viable treatment option for pembrolizumab-induced MG, owing to its rapid therapeutic effects.

Combining immune checkpoint inhibitors (ICIs) with radiation therapy (RT) has led to significant advancements in cancer treatment. However, evidence from clinical and experimental studies suggests that this combination may increase hematopoietic and lymphatic toxicity. This study aims to investigate the effects of the concurrent application of ICIs (anti-PD-1 and anti-CTLA-4) on radiation-induced hematopoietic and lymphatic injuries under standardized and controlled experimental conditions.

We used various experimental models in C57BL/6 and BALB/c mice to evaluate the impact of ICIs combined with RT on the hematopoietic system. These models involved different RT doses, regimens, and target sites in both healthy and tumor-bearing mice.

Our findings showed that the concurrent use of ICIs did not meaningfully affect post-RT pancytopenia kinetics or the regeneration of specific blood cell lineages over time. Consistently, combining RT with ICIs did not significantly enhance DNA damage in immune cells within the bloodstream. This outcome was comparable across different RT doses, regimens, and target sites and was reproducible in both tumor-bearing and nontumor-bearing mice. Additionally, there were no significant increases in late side effects, including reductions in bone marrow cell counts or megakaryocyte numbers, after combined radioimmunotherapy.

These findings suggest that combining ICIs with RT does not exacerbate hematological toxicity. This information is valuable for interpreting adverse events in clinical trials involving radioimmunotherapy and for predicting potential hematological side effects in cancer patients receiving these treatments.

A novel series of 5-phenylisoindoline derivatives were designed, synthesized, and evaluated for their activity to inhibit the interaction of PD-1/PD-L1 through the homogeneous time-resolved fluorescence assay. Meanwhile, structure-activity relationships were discussed according to both experiments and calculations. Several compounds exhibited potent activity with an IC50 value less than 10 nM, especially D6 (4.8 nM). D6 could promote IFN-γ secretion and reduce the proportion of PD-L1 late apoptosis at 100 nM in the coculture model of peripheral blood mononuclear cells and hPD-L1-FC. Beyond this, the in vitro model showed D6 could lead to the weakening of migration caused by the PD-1/PD-L1 axis. Furthermore, D6 also displayed dose-dependent and low-toxic efficacy in the MC38 mouse tumor model with the tumor growth inhibition of 52.8% (20 mg/kg, ip) and 64.4% (160 mg/kg, i.g.). Mechanistic investigations suggested that D6 could activate the immune microenvironment in the tumor. Thus, D6 is a promising small molecule lead for blocking PD-1/PD-L1.

Exosomes, characterized by their bilayer lipid structure, are crucial in mediating intercellular signaling and contributing to various physiological processes. Tumor cells produce distinct exosomes facilitating cancer progression, angiogenesis, and metastasis by conveying signaling molecules. A notable feature of these tumor-derived exosomes is the presence of programmed death-ligand 1 (PD-L1) on their surface. The PD-L1/programmed cell death receptor-1 (PD-1) signaling axis serves as a critical immune checkpoint, enabling tumors to evade immune detection and antitumor activity. The advancement of immunotherapy targeting the PD-1/PD-L1 pathway has significantly impacted the treatment landscape for non-small cell lung cancer (NSCLC). Despite its promise, evidence indicates that many patients experience limited responses or develop resistance to PD-1/PD-L1 inhibitors. Recent studies suggest that exosomal PD-L1 contributes to this resistance by modulating immune responses and tumor adaptability. This study reviews the PD-1/PD-L1 pathway's characteristics, current clinical findings on PD-L1 inhibitors in NSCLC, and exosome-specific attributes, with a particular focus on exosomal PD-L1. Furthermore, it examines the growing body of research investigating the role of exosomal PD-L1 in cancer progression and response to immunotherapy, underscoring its potential as a target for overcoming resistance in NSCLC treatment.

Immune checkpoints, such as PD-1 and CTLA-4, are crucial regulators of immune responses, acting as gatekeepers to balance immunity against foreign antigens and self-tolerance. These checkpoints play a key role in maintaining cardiac homeostasis by preventing immune-mediated damage to critical organs like the heart. In this study, we explored the involvement of PD-1 and CTLA-4 in cardiovascular complications, particularly atherosclerosis and myocarditis, which can lead to heart failure. We conducted a comprehensive analysis using animal models and clinical data to assess the effects of immune checkpoint inhibition on cardiac function. Our findings indicate that disruption of PD-1 and CTLA-4 pathways exacerbates myocardial inflammation, accelerates atherosclerotic plaque formation, and promotes the development of heart failure. Additionally, we observed that immune checkpoint inhibition in these models led to increased infiltration of T lymphocytes, higher levels of pro-inflammatory cytokines, and enhanced tissue damage. These results suggest that PD-1 and CTLA-4 are critical in preserving cardiac health, and their inhibition can result in severe cardiovascular toxicity. Our study emphasizes the need for careful monitoring of cardiovascular health in patients undergoing immune checkpoint inhibitor therapies.

Light therapy, also known as bright light therapy, is a nonpharmacological approach to treat seasonal mood disorders and a wide range of other conditions by exposure to artificial light. Bright light therapy is considered a well-tolerated and easy to administer form of treatment with relatively low costs. Our systematic review is focused on the available literature data regarding the applications of this therapy to the field of oncology. Overall, in this context light therapy has showed promising results, providing a safe and potentially effective treatment for a variety of psychological symptoms (especially sleep disturbances and fatigue, but also mood and anxiety symptoms). Thereby, taking into account the enormous impact of all these symptoms on cancer patients' health-related quality of life, the validation and integration of bright white light therapy in the therapeutic armamentarium of these patients may be potentially highly beneficial in the daily clinical practice and could hopefully lead to a more comprehensive and integrated oncology care.

Immune checkpoint receptors and ligands such as cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1) and ligand-1 (PD-L1) are widely expressed on immune and non-immune cells and fine tune the activation level of immune cells, thus, enabling, preventing, or terminating immune responses. Blockade of CTLA-4, PD-1 or PD-L1 by checkpoint inhibitors (CIs), unleashing immune responses, has become a mainstay in the treatment of diverse types of cancer. The induction of autoinflammatory, yet unspecific tissue damage in diverse organs is called an immune related adverse event (irAE), a class side-effect of CIs and may require the discontinuation of immunotherapy. Among frequent skin rashes, CIs targeting the PD-L1/PD-1 axis can elicit the IgG autoantibody- and granulocyte-driven bullous pemphigoid (BP) in about 0.3% to 0.6% of treated patients. Pathogenesis of BP requires a complex cellular inflammatory response after anti-BP180 autoantibody binding to the dermal epidermal junction. The prevalence of autoantibodies against BP180 in healthy blood donors of approximately 0.52% equals the prevalence of irBP among treated cancer patients, underlining the potential relevance of the PD-1 mediated regulation of tissue inflammation for spontaneous BP. If skin rashes appear during CI therapy, biopsies should be taken and examined by histopathological and direct immunofluorescence microscopy.

Sulforaphane (SFN), a natural compound found in cruciferous vegetables, possesses well-documented antitumor properties. However, the precise functions and mechanisms of SFN in cancer suppression remain poorly understood. Here we provide evidence to demonstrate that SFN exerts more pronounced antitumor effects in immunocompetent mice compared to immunodeficient mice, suggesting the involvement of the host immune system in SFN-mediated tumor suppression. Furthermore, we reveal that SFN primarily acts through CD8+ cytotoxic T lymphocytes (CTLs) to enhance antitumor immunity by blocking the IFN-γ-mediated induction of PD-L1, a critical immune checkpoint receptor expressed in cancer cells. Importantly, our findings indicate that the suppression of PD-L1 expression by SFN is independent of the NRF2 protein stabilization pathway. Instead, SFN inhibits IFN-γ-mediated activation of STAT1, a key transcription factor involved in PD-L1 induction. Mechanistically, SFN covalently modifies specific cysteine residues (C155 and C174) on STAT1, resulting in the inhibition of its transcriptional activity. Notably, SFN-mediated downregulation of PD-L1 contributes to its antitumor immune effects, as demonstrated by enhanced anti-CTLA-4-mediated cytotoxicity. These findings indicate that SFN's antitumor effect extends beyond its direct cytotoxic properties, as it also actively engages the host immune system. This underscores SFN's immense potential as an immune-modulating agent in cancer therapy.

Monoclonal antibodies (mAbs) have transformed cancer treatment by providing highly targeted and effective therapies that specifically attack cancer cells, thus reducing the likelihood of adverse events (AEs) in patients. mAbs exert their action through various mechanisms, such as receptor blockade, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and inhibition of immune checkpoints (eg, PD-1, PD-L1, and CTLA-4). These therapies have led to significant improvements in the treatment of several cancers, including HER2-positive breast cancer, non-small cell lung cancer (NSCLC), and melanoma. The efficacy of mAb therapy in cancer treatment is influenced by various intrinsic and extrinsic factors, such as environmental exposures, psychosocial factors, infection status, ways of life, and tumor microenvironment (TME), all of which can impact immune responses and treatment outcomes. Notably, the therapeutic benefits of mAbs are often accompanied by immune-related AEs (irAEs), which can vary from mild to severe and affect multiple organ systems. The dual nature of mAbs-stimulating antitumor immune responses while also inducing immune-related side effects-presents a notable challenge in clinical practice. This review highlights the importance of proactive strategies for managing irAEs, such as early detection, corticosteroid use, targeted immunosuppressive treatments, and the urgent need for reliable predictive biomarkers to improve treatment outcomes. Advancements in the prevention, prediction, and management of irAEs are essential to enhance the safety and effectiveness of mAb-based therapies, ultimately aiming to improve cancer patient outcomes.

Vitamin C (VitC) has elicited considerable interest regarding its potential role in cancer therapy; however, its effects on tumor immunity remain unclear. In colorectal cancer (CRC), although anti-PD-1/PD-L1 therapies demonstrate promise, their efficacy is still constrained. Our prior research demonstrated that VitC can inhibit tumor growth by suppressing the Warburg effect. This study aims to explore the effects of high-dose VitC on PD-L1 expression in CRC, focusing on its underlying mechanisms and potential for enhancing immunotherapy. We found that VitC inhibits aerobic glycolysis in HCT116 cells while also downregulating PD-L1 expression. Further investigations indicated that this process is mediated by VitC's activation of AMPK, which downregulates HK2 and NF-κB, ultimately resulting in reduced PD-L1 expression and increased T cell infiltration. Notably, we observed that VitC and the PD-L1 monoclonal antibody atezolizumab exhibit comparable tumor-inhibiting abilities, and their combined use further enhances this efficacy. In conclusion, our results demonstrate that high-dose VitC activates AMPK, downregulates PD-L1 expression, mitigates immune evasion, and suppresses tumor growth. This provides a promising strategy for optimizing immunotherapy in CRC.

Cancer-related cognitive decline refers to a deterioration in cognitive function affecting adults with cancer at any stage of their cancer journey. Older adults are at increased risk of cognitive decline. As the indications for immune checkpoint inhibitors expand in the treatment of cancer, understanding the potential complicating cognitive issues experienced by those receiving this therapy will be important. The aim of this scoping review is to identify the literature regarding immune checkpoint inhibitors and subjective/objective decline, to identify evidence in older adults, differences between older and younger adults, and outline areas for further research. Four large electronic databases were searched. Records were screened using standardised methodology. Ten studies were identified that met the inclusion criteria for review. Six studies objectively evaluated cognitive function in adults receiving ICI treatment; eight studies performed subjective cognitive assessments. There were differences identified in the cognitive assessment tools used and the methodology between studies. Few studies reported on age-dependent findings. The results of this scoping review highlight the need for further research in this area using standardised methodology and testing, with a particular focus on the cognitive outcomes of older adults who may be at increased risk of developing cognitive decline while on treatment.

Trastuzumab deruxtecan (T-DXd) has been approved to treat various tumors. While most adverse events (AEs) associated with T-DXd are manageable, interstitial lung disease (ILD)/pneumonitis is a notable AE of special concern. This review describes the incidence, severity, and management of T-DXd-induced ILD/pneumonitis across different tumors. We conducted a systematic search of PubMed, Embase, Cochrane Library, and Web of Science for literature published up to 13 September 2024, regarding the use of T-DXd in the treatment of HER2-positive tumors. Studies included were clinical trials involving HER2-positive tumors with reported ILD/pneumonitis cases.The main data extracted from the full-text articles included the incidence and severity of T-DXd-induced ILD. 18 studies involving 3380 patients with various advanced solid malignancies were included in our review. The overall incidence of adjudicated drug-related ILD/pneumonitis was 12.40%. Although most ILD/pneumonitis cases were low-grade, the risk of ILD/pneumonitis-related death should not be overlooked. Given the prolonged exposure to the drug, careful monitoring and management of T-DXd-induced ILD/pneumonitis are critical. Management strategies include dose reduction, treatment interruption, discontinuation, corticosteroids, and supportive care. Further research is needed to clarify the risk factors and mechanisms underlying T-DXd-induced ILD/pneumonitis. This review highlights critical gaps in understanding the risk factors and mechanisms of T-DXd-induced ILD, underscoring the need for further research.

The network meta-analysis (NMA) was aimed to compare and assess the effectiveness of programmed cell death 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) inhibitor monotherapy or combination therapy with other agents for individuals with advanced or recurrent endometrial cancer (EC).

The NMA was registered on the PROSPERO website (ID: CRD42024545968) and multiple databases were queried to retrieve the articles. It assessed the progression-free survival (PFS) and overall survival (OS) of persons with advanced or recurrent EC, as well as those with deficient mismatch repair (dMMR) and proficient mismatch repair (pMMR) in terms of PFS.

The NMA included 12 studies involving a total of 4,515 patients. Compared to chemotherapy, the PD-1/PD-L1 inhibitor monotherapy (hazard ratio [HR], 0.59; 95% confidence interval [CI]: 0.44-0.78) in PFS, combination therapy with poly (ADP-ribose) polymerase inhibitors (PARPis) (HR, 0.53; 95% CI: 0.32-0.89) or with antiangiogenic agents (HR, 0.48; 95% CI: 0.25-0.83) all showed significant improvements in PFS. PD-1/PD-L1 inhibitor monotherapy resulted in a significantly higher OS (HR, 0.61; 95% CI: 0.37-0.97) compared to chemotherapy. Combination therapy with antiangiogenic agents demonstrated the highest efficacy in extending PFS, while the combination with PARPis had the best performance in extending OS. Patients with dMMR and pMMR subtypes derive greater benefits from PD-1/ PD-L1 inhibitor monotherapy and PD-1/PD-L1 inhibitors combined with PARPis respectively.

Monotherapy with PD-1/PD-L1 inhibitors and combination therapies with PARPis or antiangiogenic agents demonstrate significant potential for individuals with advanced or recurrent EC.

Lung cancer patients co-harboring EGFR Ex19del mutation and MET de novo amplification is extremely uncommon. Thus, the optimal therapeutic strategies, treatment-related complications, and prognosis for such patients remain unclear. Herein, we describe a case of patient co-harboring EGFR Ex19del mutation and MET de novo amplification who presented targeted (almonertinib)-induced interstitial lung disease (ILD). We propose that patients with EGFR Ex19del mutation and MET de novo amplification may benefit more from dual-targeted therapy than pemetrexed and carboplatin chemotherapy along with bevacizumab. However, dual-targeted therapy may increase the risk of ILD, so it is important to be alert to targeted-induced ILD, and unexplained fever may be an early warning signal for targeted-induced ILD, especially almonertinib-induced ILD. Timely intervention is needed to avoid greater harm when ILD occurs and, when ILD is effectively controlled, seize the opportunity to rechallenge the dual-targeted therapy may contribute to a better prognosis. In addition, the patients with targeted-induced ILD in the past need more rigorous monitoring and follow-up in the process of rechallenging the targeted drug therapy.

Immune checkpoint inhibitor-induced type 1 diabetes (ICI-T1D) is a rare immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). This retrospective study aimed to characterize the clinical features and glucose patterns of ICI-T1D in Chinese individuals and compare them with those of traditional T1D. Between January 2019 and April 2024, 15 patients diagnosed with ICI-T1D were consecutively enrolled. Continuous glucose monitoring (CGM) data from 7 of these patients were compared with data from 14 traditional T1D patients, matched for age, sex, fasting C-peptide levels, and diabetes duration. Median time from ICI initiation to T1D onset was 16 weeks (IQR, 6-96). Notably, T1D developed in four participants at 144, 112, 108, and 96 weeks after PD-1 treatment, respectively. Three ICI-T1D had pre-existing type 2 diabetes (T2D). Moreover, two had concurrent hypothyroidism and adrenal insufficiency alongside ICI-T1D. CGM analysis suggested that ICI-T1D exhibited a higher overall coefficient of variation (CV) (36.3 ± 4.8% vs. 28.2 ± 6.5%; p = 0.009), a greater CV during the night (37.4 ± 8.4% vs. 23.4 ± 7.3%; p = 0.001), and an increased standard deviation (SD) during the night (3.3 ± 0.8 mmol/L vs. 2.1 ± 1.1 mmol/L; p = 0.017) compared to those with traditional T1D. The study highlighted diverse clinical presentations of ICI-T1D, including delayed onset and multiple endocrine organs dysfunctions after ICI treatment. Consequently, long-term glucose monitoring and early identification are crucial. Furthermore, the observed greater glucose variability in ICI-T1D emphasizes the critical importance of diabetes education and personalized insulin regimen.

Melanoma, an aggressive skin cancer, presents significant therapeutic challenges. Consequently, innovative treatment strategies beyond conventional chemotherapy, radiation, and surgery are actively explored. This review discusses the evolution of immunotherapy in advanced melanoma, highlighting PD-1/PD-L1 inhibitors, mRNA vaccines, Talimogene Laherparepvec (T-VEC), and tumor-infiltrating lymphocyte (TIL) therapies. PD-1/PD-L1 inhibitors such as pembrolizumab and nivolumab block immune checkpoints, promoting T-cell cytotoxic activity and improving overall survival in patients with advanced melanoma. T-VEC, a modified oncolytic herpes virus, promotes a systemic anti-tumor response while simultaneously lysing malignant cells. mRNA vaccines, such as Moderna's mRNA-4157/V940, take advantage of malignant-cell-specific neoantigens to amplify the adaptive immune response while protecting healthy tissue. TIL therapy is a form of therapy involving ex vivo expansion and reinfusion of the patient's tumor-specific lymphocytes and has been shown to provide durable tumor control. While these therapies have demonstrated promising clinical outcomes, challenges such as tumor resistance, high financial burden, and limited accessibility pose challenges to their widespread use. This review explores combination therapies such as PD-L1 inhibitors with mRNA vaccines, or TIL therapy, which aim to enhance treatment through synergistic approaches. Further research is required to optimize these combinations, address barriers preventing their use, and control adverse events.

This study aims to evaluate the hemorrhage risk in solid tumor patients receiving angiogenesis inhibitors (AGIs), immune checkpoint inhibitors (ICIs), and their combination using the FDA Adverse Event Reporting System (FAERS) database.

Data from Q1 2011 to Q4 2023 were extracted from the FAERS database for solid tumor patients treated with AGIs, ICIs, or their combination. A disproportionality analysis was conducted by calculating the reporting odds ratio (ROR) and corresponding 95% confidence interval (CI), as well as the Proportional Reporting Ratio (PRR), to identify potential safety signals. To assess whether the hemorrhage risk is higher with combination therapy compared to monotherapy, additive and multiplicative models were employed to evaluate the interactions between combination and single-agent treatments.

The combination of AGIs and ICIs significantly increased the risk of hemorrhagic adverse events, particularly tumor and pulmonary hemorrhage. Hemorrhagic events were common in females (50.97%) and older patients (aged 64+), frequently occurring within the first 30 days of treatment (38.11%). Gingival hemorrhage (ROR 3, PRR 418.9) and tumor hemorrhage (ROR 9.65, PRR 1893.36) were most common in the AGI group, while tumor hemorrhage (ROR 9.49, PRR 1350.78) and pulmonary hemorrhage (ROR 2.6, PRR 98.97) were prominent in the ICI group. In the combination group, esophageal variceal hemorrhage (ROR 40.72, PRR 2344.72) and tumor hemorrhage (ROR 19.31, PRR 1056.63) exhibited significantly increased risks Additive and multiplicative models indicated that the excess risk (RDAB = 0.01025, P<0.001) and relative risk (RRAB = 1.99277, P<0.001) of combination therapy were significantly higher than those of monotherapy, suggesting a positive interaction between the drugs that further increases the risk of hemorrhage.

Our study demonstrates that the combination of AGIs and ICIs significantly raises the risk of hemorrhage, underscoring the urgent need for enhanced monitoring protocols in clinical practice to improve treatment efficacy and safety.

The interaction between programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) constitutes a critical immune checkpoint pathway that leads to immune tolerance in cancer cells and impacts antitumor treatment. Monoclonal antibody blockade of the PD-L1 immunoinhibitory pathway has demonstrated significant and lasting clinical antitumor responses. Furthermore, PD-L1 serves as an important biomarker for predicting the effectiveness of immune checkpoint inhibitors (ICIs). To date, numerous studies based on monoclonal antibodies have been carried out to detect the expression levels of PD-L1 and predict the antitumor effectiveness of PD-L1 ICIs. However, due to the deficiencies of monoclonal antibodies, researches of PD-L1 peptides have received increasing attention. PD-L1 peptides present promising candidates due to their advantages, including reduced manufacturing costs, enhanced stability, decreased immunogenicity, faster clearance and improved tumor or organ penetration, thereby offering broad application prospects in cancer immunoimaging and immunotherapy. In this review, we analyze the existing evidence on PD-L1 peptides in cancer immunoimaging and immunotherapy. First, the design techniques of different types of PD-L1 targeting peptides and their strengths and weaknesses are briefly introduced. Second, the recent advancements in immunoimaging and the development trends in immunotherapy are summarized. Finally, the existing challenges and future directions in this field are comprehensively deliberated.

Melanoma, a malignant skin tumor, presents significant treatment challenges, particularly in unresectable and metastatic cases. While immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have brought new hope, their efficacy is limited by low response rates and significant immune-mediated adverse events (irAEs). Through multi-omics data analysis, it is discovered that the spatial co-localization of CD73 and PD-L1 in melanoma correlates with improved progression-free survival (PFS), suggesting a synergistic potential of their inhibitors. Building on these insights, a novel therapeutic strategy using calcium phosphate (CaP) nanoparticles is developed for the co-delivery of aPD-L1 and APCP, a CD73 inhibitor. These nanoparticles, constructed via a biomineralization method, exhibit high drug-loading capacity and pH-responsive drug release. Compared to free aPD-L1, the CaP-delivered aPD-L1 effectively avoids systemic side effects while significantly enhancing anti-tumor efficacy, surpassing even a 20-fold dose of free aPD-L1. Furthermore, the co-delivery of aPD-L1 and APCP via CaP nanoparticles demonstrates a synergistic anti-tumor effect, with substantial immune activation and prevention of tumor recurrence through immune memory effects. These findings suggest that the co-delivery of aPD-L1 and APCP using CaP nanoparticles is a promising approach for improving melanoma immunotherapy, achieving enhanced efficacy and reduced toxicity.

Hemophagocytic lymphohistiocytosis (HLH) is a severe and often lethal inflammatory syndrome characterized by excessive immune activation leading to fever, cytopenias, and multiorgan involvement. Immune checkpoint inhibitors (ICIs) are central to many contemporary cancer regimens, but their use is associated with immune-related adverse events. Here, we report a case of ICI-induced HLH successfully treated with single agent dexamethasone and provide a scoping review of the literature for cases of ICI-induced HLH with a focus on treatment strategies and outcomes. Using the Medline database, we searched for cases of ICI-associated HLH, with a total of 51 cases reported between 2017 and 2023. Our results underscore the severe nature of this disease, with a 13.7 % mortality rate across 51 case reports. Treatment strategies for ICI-induced HLH were variable: steroids alone (56.9 %), steroids with etoposide (17.6 %), steroids with tociluzumab (11.8 %), among other combinations. Our literature review indicates that steroids alone may be sufficient treatment in some cases of ICI-HLH, with comparable mortality with steroids alone (n = 29) (13.8 %) to that of cases treated with both steroids and immunomodulators (n = 15, 13.3 %). Moreover, all patients treated with steroids and tocilizumab survived (n = 6), suggesting that tocilizumab may be a reasonable next line of therapy when steroid monotherapy proves inadequate. We propose an outline for investigation and treatment of this rare complication of ICI use. Finally, we discuss possible future approaches to develop evidence-based strategies for the diagnosis and management of ICI-induced HLH including the importance of integrating the role of patient community involvement.

Patients with melanoma receiving immunotherapy with immune-checkpoint inhibitors often experience immune-related adverse events, cancer-related fatigue, and emotional distress, affecting health-related quality of life (HRQoL) and clinical outcome to immunotherapy. eHealth tools can aid patients with cancer in addressing issues, such as adverse events and psychosocial well-being, from various perspectives.

This study aimed to explore the effect of the Cancer Patients Better Life Experience (CAPABLE) system, accessed through a mobile app, on HRQoL compared with a matched historical control group receiving standard care. CAPABLE is an extensively tested eHealth app, including educational material, remote symptom monitoring, and well-being interventions.

This prospective pilot study compared an exploratory cohort that received the CAPABLE smartphone app and a multisensory smartwatch for 6 months (intervention) to a 2:1 individually matched historical prospective control group. HRQoL data were measured with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 at baseline (T0), 3 months (T1), and 6 months (T2) after start of treatment. Mixed effects linear regression models were used to compare HRQoL between the 2 groups over time.

From the 59 eligible patients for the CAPABLE intervention, 31 (53%) signed informed consent to participate. Baseline HRQoL was on average 10 points higher in the intervention group compared with controls, although equally matched on baseline and clinical characteristics. When correcting for sex, age, disease stage, and baseline scores, an adjusted difference in fatigue of -5.09 (95% CI -15.20 to 5.02, P=.32) at month 3 was found. No significant nor clinically relevant adjusted differences on other HRQoL domains over time were found. However, information satisfaction was significantly higher in the CAPABLE group (β=8.71, 95% CI 1.54-15.88, P=.02).

The intervention showed a limited effect on HRQoL, although there was a small improvement in fatigue at 3 months, as well as information satisfaction. When aiming at personalized patient and survivorship care, further optimization and prospective investigation of eHealth tools is warranted.

Antibody-based checkpoint inhibitors have achieved great success in cancer immunotherapy, but their uncontrollable immune-related adverse events remain a major challenge. In this study, we developed a tumor-activated nanoparticle that is specifically active in tumors but not in normal tissues. We discovered a short anti-PD-L1 peptide that blocks the PD-1/PD-L1 interaction. The peptide was modified with a PEG chain through a novel matrix metalloproteinase-2 (MMP-2)-specific cleavage linker. The modified TR3 peptide self-assembles into a micelle-like nanoparticle (TR3-M-NP), which remains inactive and unable to block the PD-1/PD-L1 interaction in its native form. However, upon cleavage by MMP-2 in tumors, it releases the active peptide. The TR3-M-NP5k nanoparticle was specifically activated in tumors through enzyme-mediated cleavage, leading to the inhibition of tumor growth and extended survival compared to control groups. In summary, TR3-M-NP shows great potential as a tumor-responsive immunotherapy agent with reduced toxicities. STATEMENT OF SIGNIFICANCE: In this study, we developed a bioactive peptide-based checkpoint inhibitor that is active only in tumors and not in normal tissues, thereby potentially avoiding immune-related adverse effects. We discovered a short anti-PD-L1 peptide, TR3, that blocks the PD-1/PD-L1 interaction. We chemically modified the TR3 peptide to self-assemble into a micelle-like nanoparticle (TR3-M-NP), which itself cannot block the PD-1/PD-L1 interaction but releases the active TR3 peptide in tumors upon cleavage by MMP-2. In contrast, the nanoparticle is randomly degraded in normal tissues into peptides fragments that cannot block the PD-1/PD-L1 interaction. Upon intraperitoneal injection, TR3-M-NP5k was activated specifically in tumors through enzyme cleavage, leading to the inhibition of tumor growth and extended survival compared to the control groups. In summary, TR3-M-NP holds significant promise as a tumor-responsive immunotherapy agent with reduced toxicities. The bioactive platform has the potential to be used for other types of checkpoint inhibitor.

Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are critical immune checkpoints in cancer biology. Multiple small-molecule drugs have been developed as inhibitors of the PD-1/PD-L1 axis. Those drugs promote the formation of PD-L1 homodimers, causing their stabilization, internalization, and subsequent degradation. Drug repurposing is a strategy that expedites the clinical translation by identifying new effects of drugs with clinical use. Herein, we aimed to repurpose drugs as inductors of PD-L1 homodimerization and, therefore, as potential inhibitors of PD-L1.

We generated a hybrid pharmacophore model by analyzing the structures of reported ligands that induce PD-L1 homodimerization and their target-binding mode. Pharmacophore-matching compounds were selected from a chemical library of Food and Drug Administration (FDA)-approved drugs. Their binding modes to PDL1 homodimers were assessed by molecular docking and the stability of the complexes and the corresponding binding energies were evaluated by molecular dynamics (MD) simulations. Finally, the activity of one drug as promoter of PD-L1 homodimerization was assessed in protein crosslinking assays.

We identified 12 pharmacophore-matching compounds, but only 4 reproduced the binding mode of the reference inhibitors. Further characterization by MD showed that pranlukast, an antagonist of leukotriene receptors that is used to treat asthma, generated stable and energy-favorable interactions with PD-L1 homodimers and induced homodimerization of recombinant PD-L1.

Our results suggest that pranlukast inhibits the PD-1/PD-L1 axis, meriting its repurposing as an antitumor drug.

Prostate cancer is one of the most common malignant tumors in men, which seriously threatens the survival and quality of life of patients. At present, there are serious limitations in the treatment of prostate cancer, such as drug tolerance, drug resistance and easy recurrence. Sonodynamic therapy and chemodynamic therapy are two emerging tumor treatment methods, which activate specific drugs or sonosensitizers through sound waves or chemicals to produce reactive oxygen species and kill tumor cells. Nanomaterials are a kind of nanoscale materials with many excellent physical properties such as high targeting, drug release regulation and therapeutic monitoring. Sonodynamic therapy and chemodynamic therapy combined with the application of nanomaterials can improve the therapeutic effect of prostate cancer, reduce side effects and enhance tumor immune response. This article reviews the application progress of nanomaterials in the treatment of prostate cancer, especially the mechanism, advantages and challenges of nanomaterials in sonodynamic therapy and chemodynamic therapy, which provides new ideas and prospects for research in this field.

Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint protein that facilitates tumor immune evasion. While antibody-based PD-1/PD-L1 inhibitors have shown promise, their limitations necessitate the development of alternative therapeutic strategies. This work addresses these challenges by developing a hexapeptide, KFM (Lys-Phe-Met-Phe-Met-Lys), capable of both directly downregulating PD-L1 and self-assembling into a ROS-responsive supramolecular hydrogel. This dual functionality allows Gel KFM to function as a localized drug delivery system and a PD-L1 inhibitor. Loading the hydrogel with mitoxantrone (MTX) and metformin (MET) further enhances the therapeutic effect by combining chemotherapy with PD-L1 downregulation. In vitro and in vivo studies demonstrate significant tumor growth inhibition, increased CD8+ T cell infiltration, and reduced intratumoral PD-L1 expression following peritumoral administration. Mechanistically, KFM promotes PD-L1 degradation via a ubiquitin-dependent pathway. This "carrier-free" delivery system expands the role of supramolecular hydrogels beyond passive carriers to active immunotherapeutic agents, offering a promising new strategy for cancer therapy.

Although the incidence and outcomes of rituximab-induced interstitial lung disease (RILD) have been partially reported, there are no systematic studies on the characteristics and types of RILD. This study aimed to investigate the clinical characteristics, bronchoalveolar lavage (BAL) findings, and treatment course of RILD in patients with non-Hodgkin lymphoma. We retrospectively analyzed the data from 321 patients with non-Hodgkin lymphoma who developed RILD between 2020 and 2022. The extent, distribution, and radiologic patterns of interstitial lung disease were determined using high-resolution computed tomography of the chest. BAL was performed in 299 (93.1%) patients to determine cellular distribution patterns and identify pathogenic microorganisms using metagenomic next-generation sequencing. All patients received combination therapy, with cyclophosphamide, doxorubicin, vincristine, and prednisone being the most commonly administered regimens. The median time from treatment to RILD development was 1.7 months. In the 217 patients who underwent metagenomic next-generation sequencing, 179 pathogenic microorganisms were detected, including 77 (43.0%) bacteria, 45 (25.1%) viruses, 28 (15.6%) Pneumocystis jirovecii strains, 17 (9.5%) fungi, 6 (3.5%) Mycobacterium tuberculosis, and 6 (3.5%) atypical pathogens. All RILD diagnoses were based on multidisciplinary team discussions and compliance with international standards. In conclusion, RILD exhibits a range of radiological and BAL patterns, reflecting different interstitial lung disease types. The most common patterns of RILD are infectious lung disease, organizing pneumonia, and nonspecific interstitial pneumonia. These findings enhance the understanding of RILD in patients with non-Hodgkin lymphoma and serve as a reference for best management guidelines in these patients.