Currently, the use of immune checkpoint inhibitors (ICIs) has shown notable clinical efficacy in treating various malignant tumors, significantly improving patient prognosis. However, while ICIs enhance the body's anti-tumor effects, they can also trigger immune-related adverse events (irAEs), with ICI-associated colitis being one of the more prevalent forms. This condition can disrupt treatment, necessitate drug discontinuation, and adversely affect therapeutic outcomes. In severe cases, irAEs may even become life-threatening. A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain, which can arise both during and even after completion of ICI treatment. Early identification, multidisciplinary management, and continuous monitoring of patients are essential steps to further improve outcomes.

Retinol-binding protein 4 (RBP4) is primarily recognized for its role in retinoid transport, but has recently been implicated in cancer progression and prognosis. However, a comprehensive pan-cancer analysis of RBP4's expression, prognostic significance, and functional associations across various cancers is lacking.

We conducted a pan-cancer analysis of RBP4 using data from public databases. RBP4 expression levels were examined in 33 tumor types, and correlations with clinical outcomes, immune cell infiltration, DNA methylation, and gene mutations were assessed. Enrichment analyses of RBP4 and its co-expressed genes were performed to explore associated biological pathways. Additionally, in vitro experiments were conducted to assess the effects of RBP4 on cell migration and proliferation.

RBP4 showed differential expression between tumor and normal tissues, with downregulation in 21 cancer types and upregulation in 6. High expression levels of RBP4 were associated with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in specific cancers, notably in BRCA, HNSC, and STAD, whereas it was a favorable prognostic factor in cancers such as KIRP and MESO. RBP4 expression was also associated with immune cell infiltration, particularly with CD4+ Th2 cells and immune checkpoint genes. DNA methylation analysis suggested that the methylation of RBP4 may play a role in its regulatory mechanisms across cancer types. Enrichment analyses revealed that RBP4 and its co-expressed genes are involved in metabolism-related pathways and immune regulation. Functional assays indicated that RBP4 knockdown promoted tumor cell migration and proliferation.

This study provides a comprehensive pan-cancer analysis of RBP4, identifying its prognostic potential and possible involvement in tumor immunity and metabolism. Our findings suggest that RBP4 could serve as a novel biomarker and therapeutic target in cancer, although further experimental studies are required to elucidate its precise mechanisms in specific cancer types.

Soluble vector family member 6 (SLC2A6) has been implicated in the aggressiveness and poor prognosis of various cancers, yet its specific role in hepatocellular carcinoma (HCC) remains to be fully elucidated. This study utilized multiple databases to investigate the relationship between SLC2A6 expression and clinical stage, methylation status, drug sensitivity, immune infiltration, and immune checkpoint regulation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. Furthermore, in vitro and in vivo experiments were performed to assess the impact of SLC2A6 knockout on the proliferation, migration, invasion, and underlying mechanisms in hepatocellular carcinoma (LIHC) cells. SLC2A6 expression was significantly correlated with tumor prognosis, clinical stage, and methylation levels, and was found to influence immune cell infiltration and immune checkpoint gene expression. In LIHC, SLC2A6 was associated with key biological processes, including the cell cycle, P53 signaling, and ferroptosis. Knockdown of SLC2A6 markedly suppressed the proliferation, migration, and invasion of HCC cells, with this inhibition being closely tied to the ferroptosis pathway. SLC2A6 plays a pivotal role in the regulation of pan-cancer processes, particularly in tumor prognosis and immune-related mechanisms. In LIHC, it emerges as a potential prognostic biomarker and therapeutic target for the regulation of ferroptosis, offering new insights for targeted cancer therapies.

Immune-related adverse events (irAEs) induced by immune checkpoint inhibitors are difficult to predict and can lead to severe events. Although it is important to develop strategies for the early detection of severe irAEs, there is a lack of evidence on irAEs associated with ipilimumab plus nivolumab therapy for metastatic renal cell carcinoma (RCC). Therefore, this study aimed to investigate the association between eosinophil and severe irAEs in patients receiving ipilimumab plus nivolumab therapy for RCC.

In this retrospective study, 161 patients receiving ipilimumab plus nivolumab therapy for RCC were divided into three groups based on whether they experienced

Results

Although the eosinophil in the baseline samples did not differ between the severe irAE and non-irAE groups (2.8% vs. 2.5%, P = 0.75), regarding the 2-week samples, the eosinophil was significantly higher in the severe irAE group (mean, 6.6% vs. 3.3%; P < 0.05). Multivariate analysis showed that an eosinophil of ≥3.0% was a risk factor for severe irAEs (odds ratio, 6.01). Median progression-free survival (mPFS), mPFS from the start of ipilimumab plus nivolumab therapy to second-line therapy (mPFS2), and median overall survival (mOS) were the shortest in the non-irAE group. Although the mPFS did not differ between the severe and non-severe irAE groups (9.2 vs 14.2 months, P = 0.45), notably, mPFS2 and mOS in the former group tended to be shorter than those in the latter group (mPFS2: 29.2 vs not reached, P = 0.10; mOS: 36.9 vs 52.3 months, P = 0.06).

Discussion

An increased eosinophil 2 weeks after ipilimumab plus nivolumab therapy may be a predictor of severe irAEs, which are associated with poor prognoses, compared with non-severe irAEs among patients with RCC. We provide a novel rationale for the importance of monitoring eosinophil counts for the early detection of severe irAEs.

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Ubiquitin-specific protease 21 (USP21) belongs to the ubiquitin-specific protease family and is a member of the deubiquitinating enzyme (DUB) family. Previous research has shown that USP21 promotes cancer initiation and progression. However, there have been few pan-cancer analysis on USP21. We analyzed the expression levels of USP21 mRNA and protein in various human tumor tissues using several public databases such as The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), and Human Protein Atlas (HPA). Kaplan-Meier survival analyses were utilized to test the effect of USP21 on overall survival (OS) and progression-free interval (PFS) of these tumor patients. Our study demonstrated that USP21 was differentially expressed between normal and malignant tissues, conferring a notable value in evaluation of prognosis and diagnosis. In addition, enrichment and correlation analyses linking USP21 with immune features such as immune-cell-infiltration rate and immune-checkpoint-gene expression indicated that USP21 is an applicable immunotherapeutic marker for liver cancer. To further elucidate the role of USP21, we downregulated its expression in hepatocellular carcinoma cells and identified a remarkable decrease in expression of the immune checkpoint CD276, which contributes to the immune escape of tumor cells by suppressing the immune system. Together, our results indicated a promising potential of USP21 for future tumor prevention.

Gastrointestinal (GI) toxicities are among the most common and potentially severe immune-related adverse events (irAEs), and data on risk factors remain limited. This study aimed to identify risk factors for GI-irAEs in patients treated with ICIs.

We conducted a retrospective analysis of patients with any type of malignant tumor who received ICIs between January 2020 and January 2022. GI-irAEs were defined as the onset of diarrhea during the observation period. Univariate analysis was employed to explore associations between GI-irAEs and patient characteristics.

Of the 485 patients screened, 361 were eligible for analysis. GI-irAEs occurred in 29 patients (8.03%). Patients with GI cancer demonstrated shorter event-free survival (EFS) compared to those with non-GI cancer (2.33, 95% CI: 1.03-4.95; p = 0.0275). Additionally, ≥ grade 2 GI-irAEs were observed in 14 patients (3.88%). Patients with GU cancer had a significantly higher incidence of GI-irAEs (odds ratio: 3.26, 95%CI 1.21-8.71, p = 0.0497) and exhibited shorter EFS (hazard ratio: 3.07, 95%CI: 1.05-8.96; p = 0.0273) compared to those with non-GU cancer.

Our findings suggest that GI cancer may be a risk factor for developing GI-irAEs, while GU cancer may predispose patients to ≥ grade 2 GI-irAEs.

The skeletal system ranks as the third most common site for cancer metastasis, often leading to pain with nociceptive and neuropathic features. Programmed cell death protein 1 (PD-1)-targeting therapeutic antibodies offer effective cancer treatment but can cause treatment-related acute pain. Understanding the mechanisms of this pain and identifying potential interventions is still a challenge.

A murine model of bone cancer pain was established using Lewis lung carcinoma (LLC) cells, followed by intravenous administration of nivolumab, a human anti-PD-1 monoclonal antibody. Pain thresholds were measured, and micro-CT images of the skeletal system were obtained. High-throughput sequencing of the spinal cord/colon transcriptome during the acute phase of bone cancer pain and gut microbiota analysis at the end of the treatment were performed. Immunofluorescence staining and western blot experiments assessed spinal cord microglia activation and acute pain-associated molecules.

PD-1 inhibition with nivolumab protected against bone degradation initiated by LLC cell administration but consistently induced acute pain during nivolumab treatment. Spinal cord and colon transcriptomics revealed an immunopathological pattern during tumor progression and the acute pain phase, with notable changes in interleukin and S100 gene families. Gut microbiota analysis post-immunotherapy showed a decline in beneficial bacteria associated with short-chain fatty acid (SCFA) production. Activation of spinal cord microglia and enhanced glycolytic metabolism were confirmed as key factors in inducing acute pain following immunotherapy.

This study reveals that nivolumab induces acute pain by activating microglia and enhancing glycolytic metabolism in the treatment of bone cancer and uncovers connections between transcriptomic changes, gut microbiota, and acute pain following immune checkpoint blockade (ICB) treatment. It offers novel insights into the relationship between immune checkpoint blockade therapies and pain management.

Immune checkpoint blockade (ICB) has emerged as a promising immunotherapeutic approach for the treatment of various tumors. However, the efficacy of this therapy is limited in a subset of patients, and it is important to develop strategies to enhance immune responses. Studies have demonstrated a critical role of gut microbiota in regulating the therapeutic response to ICB. Gut microbiota composition, diversity, and function are mediated by metabolites, such as short-chain fatty acids and secondary bile acids, that interact with host immune cells through specific receptors. In addition, gut bacteria may translocate to the tumor site and stimulate antitumor immune responses. Therefore, maintaining a healthy gut microbiota composition, for instance through avoiding the use of antibiotics or probiotic interventions, can be an effective approach to optimize ICB therapy. This review summarizes the current understanding of the microbiota-immunity interactions in the context of ICB therapy, and discusses potential clinical implications of these findings.

Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity of immunotherapy were excluded. We excluded certain article types depending on whether stronger evidence was available in the literature for a specific toxicity, for example, if prospective studies were available on a topic, retrospective studies and case reports were excluded. We extracted a final 166 articles for our review and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data reporting. Risk of bias tools were not used to evaluate the extracted studies given the narrative nature of this manuscript, but each study was critically appraised by the manuscript writer. We detail the incidence, presentation, evaluation, management, and outcomes of the various GI toxicities that may arise with ICI therapy. Specifically, we discuss the characteristics of upper GI toxicity (esophagitis and gastroenteritis), lower GI toxicity (colitis), hepatobiliary inflammation, pancreatitis, and rarer forms of GI toxicity. We hope this review serves as a useful and accessible clinical tool that helps physicians familiarize themselves with the nuances of gastrointestinal/hepatic/pancreatic ICI toxicity diagnosis and management.

Esophageal cancer (EC) is a malignancy with a high incidence and poor prognosis, significantly influenced by dysbiosis in the esophageal, oral, and gut microbiota. This review provides an overview of the roles of microbiota dysbiosis in EC pathogenesis, emphasizing their impact on tumor progression, drug efficacy, biomarker discovery, and therapeutic interventions. Lifestyle factors like smoking, alcohol consumption, and betel nut use are major contributors to dysbiosis and EC development. Recent studies utilizing advanced sequencing have revealed complex interactions between microbiota dysbiosis and EC, with oral pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum promoting inflammation and suppressing immune responses, thereby driving carcinogenesis. Altered esophageal microbiota, characterized by reduced beneficial bacteria and increased pathogenic species, further exacerbate local inflammation and tumor growth. Gut microbiota dysbiosis also affects systemic immunity, influencing chemotherapy and immunotherapy efficacy, with certain bacteria enhancing or inhibiting treatment responses. Microbiota composition shows potential as a non-invasive biomarker for early detection, prognosis, and personalized therapy. Novel therapeutic strategies targeting the microbiota-such as probiotics, dietary modifications, and fecal microbiota transplantation-offer promising avenues to restore balance and improve treatment efficacy, potentially enhancing patient outcomes. Integrating microbiome-focused strategies into current therapeutic frameworks could improve EC management, reduce adverse effects, and enhance patient survival. These findings highlight the need for further research into microbiota-tumor interactions and microbial interventions to transform EC treatment and prevention, particularly in cases of late-stage diagnosis and poor treatment response.

The increased use of immune checkpoint inhibitors (ICIs) across cancer programs has created the need for standardized monitoring and management of immune-related adverse events (irAEs). Delayed recognition without appropriate treatment can have serious and life-threatening consequences. The management of irAEs presents a unique set of challenges that must be addressed at a multidisciplinary level. Although various national and international guidelines and working groups provide high-level recommendations for the management of irAEs, practical guidance is lacking. Furthermore, timely collaboration between specialists requires institutional protocols that enable the early recognition, assessment, and treatment of irAEs. Such protocols should be developed by institution specialists and include algorithms for all healthcare providers involved in the care of patients treated with ICIs. At William Osler Health System in Brampton, Ontario, practical step-by-step multidisciplinary treatment approaches with recommendations for the management of irAEs were developed in collaboration with experts across Canada. Here, we provide an in-depth description of the approaches, outlining baseline investigations prior to the initiation of ICIs, as well as the monitoring and management of irAEs based on symptoms, severity, and involved organ systems. We encourage other centres to adapt and modify our approaches according to their specific needs and requirements.

ATAD2 (ATPase Family AAA Domain-Containing 2) is highly expressed across varies tumor types, yet its common roles in tumor progression and immune interaction remain unclear. We analyzed the expression and alteration profiles of ATAD2, along with its diagnostic and prognostic role in pan-cancer, utilizing TCGA, GTEx, CPTAC, HPA, and cBioPortal databases. Furthermore, we examined the relationship between ATAD2 and immune infiltration utilizing single-cell sequencing data and TCGA database. Additionally, the expression and oncogenic functions of ATAD2 were verified in papillary thyroid carcinoma (PTC) through MTT, wound-healing, transwell, and flow cytometry assays. Our results revealed significant overexpression of ATAD2 in most cancers, strongly associated with poor prognosis. Amplification was the most frequent alteration type of ATAD2, with its mutation correlating with improved overall survival. ATAD2 was positively correlated with multiple inhibitory immune checkpoints and closely associated with the immunosuppressive microenvironment, particularly in PTC. In vitro experiments demonstrated that ATAD2 promoted the proliferation, migration, and invasion of PTC cells by activating the PI3K-AKT pathway and modulating the G1/S cell cycle checkpoint. Collectively, ATAD2 holds promise as a biomarker for pan-cancer diagnosis and prognosis, as well as a predictor of immunotherapeutic responsiveness and a therapeutic target to enhance the efficacy of existing anti-tumor immune therapies.

Immune checkpoint inhibitors (ICIs) have emerged as an integral component of the management of various cancers and have contributed to significant improvements in overall survival. Most available ICIs target anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4), and anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD1/PDL1). Gastrointestinal immune-related adverse events remain a common complication of ICIs. The predominant manifestations include diarrhea and colitis, which often manifest concurrently as immune-mediated diarrhea and colitis (IMDC). Risk factors for developing these side effects include baseline gut microbiota, preexisting autoimmune disorders, such as inflammatory bowel disease, and type of neoplasm. The hallmark symptom of colitis is diarrhea which may be accompanied by mucus or blood in stools. Patients may also experience abdominal pain, fever, vomiting, and nausea. If not treated rapidly, ICI-induced colitis can lead to serious life-threatening complications. Current management is based on corticosteroids as first-line, and immunosuppressants like infliximab or vedolizumab for refractory cases. Microbiota transplantation and specific cytokines and lymphocyte replication inhibitors are being investigated. Optimal patient care requires maintaining a balance between treatment toxicity and efficacy, hence the aim of this review is to enhance readers' comprehension of the gastrointestinal adverse events associated with ICIs, particularly IMDC. In addition to identifying the risk factors, we discuss the incidence, clinical presentation, workup, and management options of IMDC.

Immune checkpoint inhibitors (ICIs) constitute a pivotal class of immunotherapeutic drugs in cancer treatment. However, their widespread clinical application has led to a notable surge in immune-related adverse events (irAEs), significantly affecting the efficacy and survival rates of patients undergoing ICI therapy. While conventional hematological and imaging tests are adept at detecting organ-specific toxicities, distinguishing adverse reactions from those induced by viruses, bacteria, or immune diseases remains a formidable challenge. Consequently, there exists an urgent imperative for reliable biomarkers capable of accurately predicting or diagnosing irAEs. Thus, a thorough review of existing studies on irAEs biomarkers is indispensable. Our review commences by providing a succinct overview of major irAEs, followed by a comprehensive summary of irAEs biomarkers across various dimensions. Furthermore, we delve into innovative methodologies such as machine learning, single-cell RNA sequencing, multiomics analysis, and gut microbiota profiling to identify novel, robust biomarkers that can facilitate precise irAEs diagnosis or prediction. Lastly, this review furnishes a concise exposition of irAEs mechanisms to augment understanding of irAEs prediction, diagnosis, and treatment strategies.

Patients with inflammatory bowel diseases (IBDs), including both ulcerative colitis (UC) and Crohn's disease (CD), are at a higher risk of developing colorectal cancer (CRC). However, advancements in endoscopic imaging techniques, integrated surveillance programs, and improved medical therapies have led to a decrease in the incidence of CRC among IBD patients. Currently, the management of patients with IBD who have a history of or ongoing active malignancy is an unmet need. This involves balancing the risk of cancer recurrence/progression with the potential exacerbation of IBD if the medications are discontinued. The objective of this review is to provide an updated summary of the epidemiology, causes, risk factors, and surveillance approaches for CRC in individuals with IBD, and to offer practical guidance on managing IBD patients with history of previous or active cancer.

Background: FAM110B belongs to the family that has a 110 sequence similarity (FAM110) and is located in the centrosome and mitotic spindle. FAM110B has been linked to tumor cell growth in earlier research. Uncertainty exists regarding FAM110B's function within the tumor microenvironment is unclear as well as pan-cancer. Methods: In order to assess the variation in FAM110B expression within normal and pan-cancer tissues, we combined the TCGA and GTEx databases. The cBioPortal database and the GSCALite platform were used to examine the variation in genome and methylation alteration of FAM110B. Cox regression, Kaplan-Meier, and SangerBox were employed to examine the clinical features and prognosis of FAM110B and pan-cancer. The purpose of the correlational research was to investigate the associations within immunerelated genes, tumor mutation burden, microsatellite instability, immune-related genes, and immunological checkpoints and FAM110B expression. ESTIMATE, EPIC, QUANTISEQ, and MCPCOUNTER methods were used to calculate the interaction among FAM110B expression as well as the tumor immune microenvironment. The immunoinfiltration and function of FAM110B were analyzed by single-cell databases (TISCH and CancerSEA). Finally, we evaluated the sensitivity of FAM110B to small-molecule medications through GDSC and CTRP databases. Results: The transcription and protein expression of FAM110B varies significantly throughout cancer types, and this has predictive value for the prognosis of some tumors; including brain lower grade glioma (LGG), stomach adenocarcinoma (STAD), pancreatic adenocarcinoma (PAAD), etc. In the tumor microenvironment, the expression level of FAM110B was associated with immune cell infiltration, immune checkpoint immune regulatory genes, tumor mutational burden, and microsatellite fragility to a certain extent. Conclusion: This work investigates the possibility of utility of FAM110B as a marker to forecast pan-cancer immunotherapy response, providing a theoretical basis for cancer therapy.

Immune-related adverse events, particularly colitis (irAE-colitis), are significant impediments to the advancement of immune checkpoint therapy. To address this, blocking TNF-α and modulating gut microbiota are effective strategies. However, their precise roles in irAE-colitis pathogenesis and potential reciprocal relationship remain unclear. An irAE-colitis model was established to evaluate the toxicity of DICB and the efficacy of Infliximab, validated through a tumor irAE-colitis mice model. Co-administration of Infliximab with DICB mitigates colitis and enhances efficacy. Analysis of fecal samples from mice reveals altered gut microbiota composition and function induced by irAE-colitis, restored by Infliximab. Notably, Bacteriodes abundance is significantly higher in irAE-colitis. Disruption of arachidonic acid and tyrosine metabolism, and steroid hormone biosynthesis is evident. Mechanistically, a regenerative feedback loop involving DICB, TNF-α and gut microbiota underlies irAE-colitis pathogenesis. In conclusion, Infliximab shows therapeutic effects against DICB toxicity, highlighting the unforeseen roles of gut microbiota and TNF-α in irAE-colitis.

Programmed cell death 1 (PD-1) inhibitors are immune checkpoint inhibitors (ICI) that have demonstrated significant efficacy in treating various advanced malignant tumors. While most patients tolerate treatment well, several adverse drug reactions, such as fatigue, myelosuppression, and ICI-associated colitis, have been reported.

This case involved a 57-year-old male patient with ulcerative colitis complicated by hepatocarcinoma who underwent treatment with tirelizumab (a PD-1 inhibitor) for six months. The treatment led to repeated life-threatening lower gastrointestinal hemorrhage. The patient received infliximab, vedolizumab, and other salvage procedures but ultimately required subtotal colectomy due to uncontrollable massive lower gastrointestinal bleeding. Currently, postoperative gastrointestinal bleeding has stopped, the patient's stool has turned yellow, and his full blood cell count has returned to normal.

This case highlights the necessity of early identification, timely and adequate treatment of ICI-related colitis, and rapid escalation to achieve the goal of improving prognosis.

Immunotherapy has revolutionized oncology care, improving patient outcomes in several cancers. However, these therapies are also associated with typical immune-related adverse events due to the enhanced inflammatory and immune response. These toxicities can arise at any time during treatment but are more frequent within the first few months. Any organ and tissue can be affected, ranging from mild to life-threatening. While some manifestations are common and more often mild, such as dermatitis and colitis, others are rarer and more severe, such as myocarditis. Management depends on the severity, with treatment being held for >grade 2 toxicities. Steroids are used in more severe cases, and immunosuppressive treatment may be considered for non-responsive toxicities, along with specific organ support. A multidisciplinary approach is mandatory for prompt identification and management. The diagnosis is primarily of exclusion. It often relies on imaging features, and, when possible, cytologic and/or pathological analyses are performed for confirmation. In case of clinical suspicion, imaging is required to assess the presence, extent, and features of abnormalities and to evoke and rule out differential diagnoses. This imaging-based review illustrates the diverse system-specific toxicities associated with immune checkpoint inhibitors and chimeric antigen receptor T-cells with a multidisciplinary perspective. Clinical characteristics, imaging features, cytological and histological patterns, as well as the management approach, are presented with insights into radiological tips to distinguish these toxicities from the most important differential diagnoses and mimickers-including tumor progression, pseudoprogression, inflammation, and infection-to guide imaging and clinical specialists in the pathway of diagnosing immune-related adverse events.

Recently, antitumor immunotherapies have witnessed a breakthrough with the emergence of immune checkpoint inhibitors (ICIs) including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. Unfortunately, the use of ICIs has also led to the advent of a novel class of adverse events that differ from those of classic chemotherapeutics and are more reminiscent of autoimmune diseases, the immune-related adverse events (IRAEs). Herein, we performed an insight of the main IRAEs associated with ICIs, focusing on gastroenterological IRAEs and specifically on checkpoint inhibitor colitis, which represents the most widely reported IRAE to date. We comprehensively dissected the current evidence regarding pathogenesis, diagnosis, and management of ICIs-induced colitis, touching upon also on innovative therapies.

The immunotherapy revolution with the use of immune checkpoint inhibitors (ICIs) started with the clinical use of the first ICI, ipilimumab, in 2011. Since then, the field of ICI therapy has rapidly expanded - with the FDA approval of 10 different ICI drugs so far and their incorporation into the therapeutic regimens of a range of malignancies. While ICIs have shown high anti-cancer efficacy, they also have characteristic side effects, termed immune-related adverse events (irAEs). These side effects hinder the therapeutic potential of ICIs and, therefore, finding ways to prevent and treat them is of paramount importance. The current protocols to manage irAEs follow an empirical route of steroid administration and, in more severe cases, ICI withdrawal. However, this approach is not optimal in many cases, as there are often steroid-refractory irAEs, and there is a potential for corticosteroid use to promote tumour progression. This review surveys the current alternative approaches to the treatments for irAEs, with the goal of summarizing and highlighting the best attempts to treat irAEs, without compromising anti-tumour immunity and allowing for rechallenge with ICIs after resolution of the irAEs.

PD-1 (programmed Death-1) immune checkpoint inhibitors have provided significant benefits to tumor patients. However, a considerable proportion of the patients develop immune-related adverse events (irAEs), of which cutaneous irAEs (cirAEs, e.g., psoriasis) occur relatively early. This review provides an overview of the current progress in psoriasis de novo or exacerbation by PD-1 checkpoint inhibitors. It not only describes the relevant influencing factors but also theoretically analyzes the immunological mechanisms that lead to the onset or exacerbation of psoriasis. Finally, the authors present guidelines for the treatment of psoriasis de novo or exacerbation by PD-1 checkpoint inhibitors. The review is intended to assist dermatologists in the early recognition and effective individualized management of such cirAE, which is helpful to continue or adjust the tumor-targeted immunotherapy on the basis of ensuring the quality of life of tumor patients.

This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRC. Various experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtain a deeper understanding of the regulation of NFKB2 in CRC. The results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasis of CRC. NFKB2 played an important role in promoting tumor growth through CD8+ T-cell exhaustion. Moreover, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2), leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD-L1). Applying a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD-L1 expression and improved response to programmed death-1 blockade-based immunotherapy. In conclusion, the facilitated NFKB2-STAT2/PD-L1 axis may suppress immune surveillance in CRC and targeting NFKB2 may enhance the efficacy of immunotherapeutic strategies. Our results provide novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape.

The gut microbiota is hypothesized as a prognostic biomarker for cancer immunotherapy. Antibiotic-induced dysbiosis negatively affects the clinical outcomes of immunotherapy. However, the effect of dysbiosis on the efficacy and safety of Chemoimmunotherapy (chemo-IOs), the frontline standard of care, in advanced non-small cell lung cancer (NSCLC) remains unknown. We aimed to compare the efficacy and safety of chemo-IOs in patients exposed to antibiotics before treatment with those of patients who were not exposed.

We retrospectively reviewed patients with advanced NSCLC treated with first-line chemo-IOs between 2018 and 2020 at the National Cancer Center Hospital. The patients were divided into two groups: those exposed to antibiotics within 30 days before induction therapy (ABx group) and those did not antibiotics (Non-ABx group). Propensity score matching was used to control for potential confounding factors. Clinical outcomes including progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were compared.

Of 201 eligible patients, 21 were in the ABx group, and 42 were in the non-ABx group after propensity score matching. No differences in PFS or OS emerged between the two groups (ABx group vs. Non-ABx group) (PFS:7.0 months vs. 6.4 months, hazard ratio [HR] 0.89; 95% confidence interval [CI], 0.49-1.63, OS:20.4 months vs. 20.1 months, HR 0.87; 95% CI 0.44-1.71). The frequency of irAEs before propensity score matching was similar across any-grade irAEs (39.4% vs. 42.9%) or grade 3 or higher irAEs (9.1% vs. 11.3%).

Antibiotic-induced dysbiosis may not affect the efficacy of chemo-IOs in patients with advanced NSCLC.

The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2% to 40%, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.

Prostate cancer (PCa) poses a significant global health threaten. Immunotherapy has emerged as a novel strategy to augment the inhibition of tumor proliferation. However, the sole use of anti-PD-L1 Ab for PCa has not yielded improvements, mirroring outcomes observed in other tumor types.

This study employed the thin film hydration method to develop lipid nanobubbles (NBs) encapsulating chlorin e6 (Ce6) and anti-PD-L1 Ab (Ce6@aPD-L1 NBs). Our experimental approach included cellular assays and mouse immunization, providing a comprehensive evaluation of Ce6@aPD-L1 NBs' impact.

The Ce6@aPD-L1 NBs effectively induced reactive oxygen species generation, leading to tumor cells death. In mice, they demonstrated a remarkable enhancement of immune responses compared to control groups. These immune responses encompassed immunogenic cell death induced by sonodynamic therapy and PD-1/PD-L1 blockade, activating dendritic cells maturation and effectively stimulating CD8+T cells.

Ce6@aPD-L1 NBs facilitate tumor-targeted delivery, activating anti-tumor effects through direct sonodynamic therapy action and immune system reactivation in the tumor microenvironment. Ce6@aPD-L1 NBs exhibit substantial potential for achieving synergistic anti-cancer effects in PCa.

In cancer patients receiving immune checkpoint inhibitors (ICIs), there is emerging evidence suggesting a correlation between gut microbiota and immune-related adverse events (irAEs). However, the exact roles of gut microbiota and the causal associations are yet to be clarified.

To investigate this, we first conducted a univariable bi-directional two-sample Mendelian randomization (MR) analysis. Instrumental variables (IVs) for gut microbiota were retrieved from the MiBioGen consortium (18,340 participants). GWAS summary data for irAEs were gathered from an ICIs-treated cohort with 1,751 cancer patients. Various MR analysis methods, including inverse variance weighted (IVW), MR PRESSO, maximum likelihood (ML), weighted median, weighted mode, and cML-MA-BIC, were used. Furthermore, multivariable MR (MVMR) analysis was performed to account for possible influencing instrumental variables.

Our analysis identified fourteen gut bacterial taxa that were causally associated with irAEs. Notably, Lachnospiraceae was strongly associated with an increased risk of both high-grade and all-grade irAEs, even after accounting for the effect of BMI in the MVMR analysis. Akkermansia, Verrucomicrobiaceae, and Anaerostipes were found to exert protective roles in high-grade irAEs. However, Ruminiclostridium6, Coprococcus3, Collinsella, and Eubacterium (fissicatena group) were associated with a higher risk of developing high-grade irAEs. RuminococcaceaeUCG004, and DefluviitaleaceaeUCG011 were protective against all-grade irAEs, whereas Porphyromonadaceae, Roseburia, Eubacterium (brachy group), and Peptococcus were associated with an increased risk of all-grade irAEs.

Our analysis highlights a strong causal association between Lachnospiraceae and irAEs, along with some other gut microbial taxa. These findings provide potential modifiable targets for managing irAEs and warrant further investigation.

Colitis occurs in about 4% of individuals treated with rituximab. Optimal management of rituximab-induced colitis, which does not improve with cessation of the drug and supportive care alone, is poorly defined due to limited evidence. Severe refractory disease can lead to colectomy. We present a case of suspected rituximab-induced colitis occurring in a woman in her 70s suffering from rheumatoid arthritis. The patient achieved full clinical, endoscopic and histological remission of colitis with infliximab therapy. The use of biological therapy to treat rituximab-induced colitis can be a potentially organ-saving rescue therapy; however, it must be balanced against the increased risks of immunosuppression in patients already exposed to rituximab. While more evidence is required to fully understand the efficacy and risks of antitumour necrosis factor therapy in this scenario, our case provides an example of the successful use of infliximab for rituximab-induced colitis, which likely helped the patient avoid a colectomy.

Immune-checkpoint inhibitor-mediated colitis (IMC) is an increasingly recognized adverse event in cancer immunotherapy, particularly associated with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies. As this revolutionary immunotherapy gains prominence in cancer treatment, understanding, diagnosing, and effectively managing IMC becomes paramount. IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications. However, a precise picture of IMC pathophysiology is currently unavailable. Therefore, we aimed to summarize the existing data while acknowledging the need for further research. This comprehensive review explores the mechanisms underlying ICIs, gastrointestinal adverse effects, and, in particular, IMC's incidence, prevalence, and features. Our review also emphasizes the importance of recognizing IMC's distinct clinical and histopathological features to differentiate it from other forms of colitis. Furthermore, this paper highlights the urgent need for evolving diagnostic methods, therapeutic strategies, and a multidisciplinary approach to effectively manage IMC.

Tumor cells can evade immune surveillance by expressing immune checkpoint molecule ligands, resulting in effective immune cell inactivation. Immune checkpoint blockades (ICBs) have dramatically improved survival of patients with multiple types of cancers. However, responses to ICB immunotherapy are heterogeneous with lower patient response rates. The advances have established that the gut microbiota can be as a promising target to overcome resistance to ICB immunotherapy. Furthermore, some bacterial species have shown to promote improved responses to ICBs. However, gut microbiota is critical in maintaining gut and systemic immune homeostasis. It not only promotes differentiation and function of immunosuppressive immune cells but also inhibits inflammatory cells via gut microbiota derived products such as short chain fatty acids (SCFAs), tryptophan (Trp) and bile acid (BA) metabolites, which play an important role in tumor immunity. Since the gut microbiota can either inhibit or enhance immune against tumor, it should be a double-edged sword in ICBs against tumor. In this review, we discuss the effects of gut microbiota on immune cells and also tumor cells, especially enhances of gut microbiota on ICB immunotherapy. These discussions can hopefully promote the development of ICB immunotherapy.

The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2 % to 40 %, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.

A 68-year-old man developed immune-related adverse event (irAE) colitis after the initiation of nivolumab and ipilimumab combination therapy for malignant melanoma. We diagnosed the patient with grade 3 irAE colitis and started prednisolone (1 mg/kg/day). Although the symptom improved once, it worsened along with the tapering of prednisolone. Therefore, we started infliximab (IFX). However, symptoms did not improve after two doses of IFX. We discontinued IFX and initiated vedolizumab (VED). Because VED alone did not improve the symptom, we started granulocyte-monocyte apheresis (GMA). Twelve weeks after the onset, the colitis was in remission. Therefore, in addition to vedolizumab, GMA may be considered in cases refractory to treatment.

Immune checkpoint inhibitors can stimulate antitumor immunity but can also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNγ-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade.

Combination therapy with multiple tyrosine kinase inhibitors (multi-TKIs) and immune checkpoint inhibitors (ICIs) has been increasingly tested in clinical studies. This study aimed to investigate the effect of the addition of ICI to multi-TKIs on the profile of treatment-related adverse events.

An electronic database search was performed using PubMed and Web of Science to identify published clinical studies on multi-TKI monotherapy and multi-TKI plus ICI combination therapy from July 20, 2005 to July 1, 2023. The incidence rate of common adverse events caused by multi-TKI monotherapy and multi-TKI plus ICI combination therapy was obtained and compared from the viewpoints of (1) relative risk for the combination therapy vs sunitinib, (2) adverse event incidence rate by clinical trial, and (3) pooled incidence rate. The quality of the evidence was assessed with the Cochrane risk of bias tool. Meta-analysis used random effects models.

This systematic review identified 83 clinical studies involving 7951 patients. The combination therapy of multi-TKI and ICI was associated with an increased risk of diarrhea (relative risk [RR]: 1.24, 95% confidence interval [CI]: 1.15-1.33, P < .001), hypothyroidism (RR: 1.44, 95% CI: 1.11-1.87, P = .0064) and rash (RR: 1.71, 95% CI: 1.18-2.47, P = .0045) compared with multi-TKI monotherapy. The addition of ICI was suggested to decrease the risk of adverse events related to performance status.

Our study identified an increased risk of treatment-related adverse events associated with multi-TKI plus ICI combination therapy. This would help optimize the management of toxicities caused by multi-TKI plus ICI combination therapy.

Immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 inhibitors, have become the standard of care for many cancer types. However, they induce immune-related adverse events (irAEs), including neurotoxicity and hypophysitis. The incidence and outcomes of neurotoxicity and hypophysitis in patients treated with immune checkpoint inhibitors are not well established. We conducted a retrospective study of 812 patients with solid cancers who received immune checkpoint inhibitors at the University General Hospital of Ioannina between January 2018 and January 2023. We assessed demographic and clinical data, including the severity of symptoms, treatment regimen, other irAEs, resolution type and time, and death. Two patients experienced neurotoxicity and two hypophysitis. All four patients required inpatient administration and received corticosteroids or/and hormone replacement. Three patients responded to the initial therapy, experiencing full recovery, while one patient was corticosteroid-resistant, and immunoglobin G was administered. Two patients never received immunotherapy after their toxicity due to the severity of symptoms; one patient continued monotherapy with nivolumab, changing from combination therapy with ipilimumab-nivolumab, while the fourth patient continued his initial treatment with nivolumab. Our study suggests that the incidence of neurotoxicity and hypophysitis in patients treated with immune checkpoint inhibitors is low, but careful monitoring and prompt treatment with corticosteroids are necessary for effective management.