Over the last decade, the increasing global prevalence of melanoma has sparked growing interest in immunotherapies, which show significant potential against this form of skin cancer. This research aims to offer a framework to guide future studies and inspire new research directions. In this study, we used the Web of Science Core Collection to collect papers on immunotherapy and melanoma published between 2014 and 2024. With Excel and visualization tools like VOSviewer, COOC 13.2, Citespace, and Bibliometrix (R-Tool of R-Studio), we analyzed the data to spot trends and new focuses in the research. Our findings indicate a substantial surge in research activity concerning immunotherapy and melanoma between 2014 and 2024. The USA and China emerged as leading contributors, engaging in extensive and close collaborative efforts with European counterparts. Furthermore, seven of the top 10 research institutions are located in the USA, with the MD Anderson Cancer Center in Texas being the most productive. In addition, the Journal of Cancer Immunotherapy is the journal with the most articles published in the field. Professor Georgina V. Long from the Melanoma Institute at the University of Sydney was one of the most productive scholars. Keyword analysis shows that immune checkpoint inhibitors, tumor microenvironment and targeted therapies are key areas of interest for the research community. This paper uses bibliometric analysis to outline research trends and key points in immunotherapy and melanoma from 2014 to 2024, which helps understand the current research and guides future research directions.

Graves' ophthalmopathy (GO) is an autoimmune disorder that affects orbital tissues in approximately 30 % of Graves' disease patients. Single nucleotide polymorphisms (SNPs), particularly in immune-related genes, play a crucial role in the development of GO. This study investigates the association between SNPs in co-stimulatory molecules and specific clinical characteristics of GO, including laterality, orbital pain, swelling, diplopia, exophthalmos, redness, and eyelid retraction. Forty-one patients newly diagnosed with GO were analyzed. Genomic DNA was extracted from their blood, and 98 SNPs were amplified using PCR and sequenced. Candidate SNPs, selected based on prior research, were analyzed using chi-square tests and genetic models to assess genotype and allele frequency differences related to clinical manifestations. CD28 SNPs rs3181096 (C vs. T: p = 0.001) and rs3181098 (G vs. A: p = 0.002) were found to show protective effects against eyelid inflammation, while the A-allele of rs200353921(p = 0.005) increased the risk of eyelid inflammation. PDCD1 SNPs rs36084323 (C vs. T: p = 0.004) and rs41386349 (G vs. A: p = 0.005) were linked to diplopia and eyelid inflammation, respectively. The T-allele of rs6705653 in PDCD1 was found to increase the risk of diplopia (p = 0.001) but decreased the risk of eyelid retraction (p = 0.002). Other SNPs, including rs2227982 (p = 0.003) and rs2227981 (G vs. A: p = 0.001), were also associated with diplopia and eyelid retraction, highlighting the complex genetic influences on the clinical manifestations of GO. Furthermore, interactions between age, gender, and SNPs were observed in relation to GO clinical features. These findings highlight the potential regulatory roles of these genes in influencing immune responses and orbital inflammation in GO. Understanding these genetic influences could help identify predictive markers and novel therapeutic targets for GO management.

Immune checkpoint blockade therapies have markedly advanced cancer treatment by invigorating antitumor immunity and extending patient survival. However, therapeutic resistance and immune-related toxicities remain major concerns. Emerging evidence indicates that microbial dysbiosis diminishes therapeutic response rates, while a diverse gut ecology and key beneficial taxa correlate with improved treatment outcomes. Therefore, there is a growing understanding that manipulating the gut microbiota could boost therapy efficacy. This review examines burgeoning methods that target the gut microbiome to optimize therapy and innovative diagnostic tools to detect dysbiosis, and highlights challenges that remain to be addressed in the field.

Regulatory T (Treg) cells play critical roles in maintaining immune tolerance and tissue homeostasis, but impede anti-tumor immunity. Recent work has established how Treg cells metabolically adapt within the tumor microenvironment (TME), and these adaptations frequently provide a functional advantage over effector T cells. Further, enhanced Treg cell function in the TME may contribute to the limited efficacy of current immunotherapies, especially immune checkpoint blockade (ICB). Here, we review recent progress in understanding mechanisms of Treg cell heterogeneity and function in tumors, with a particular focus on cellular metabolism as an underlying factor by which Treg cells are uniquely poised to thrive in the TME and contribute to tumorigenesis. We describe how cellular metabolism and nutrient or metabolic communication shape Treg cell lineage identity and function in the TME. We also discuss the interplay between ICB and Treg cell metabolism and function, and highlight current strategies targeting Treg cell metabolism specifically in the TME. Understanding metabolic control of intratumoral Treg cells provides excellent opportunities to uncover new or combination therapies for cancer.

Hepatocellular carcinoma (HCC) is a global health concern because of its rising prevalence and high fatality rates. Conventional treatments for advanced HCC (aHCC) have limited success, emphasizing the need for novel treatment options. Radiotherapy (RT) treatments, such as stereotactic body radiation and proton therapy, improve local tumor management via precision targeting. Moreover, immune checkpoint inhibitors (ICIs) that target the programmed cell death protein 1(PD-1)/PD ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) pathways have promise for systemic antitumor effectiveness. The combination of RT and ICIs takes advantage of their complementary mechanisms: RT kills immunogenic cells and controls the tumor microenvironment to increase antigen presentation, whereas ICIs enhance and maintain antitumor immune responses. This combination enhances tumor regression and immune response in aHCC, improving response rate and progression-free survival with manageable safety. The present review aimed to summarize the rationale for combining RT + ICIs in patients with aHCC and clinical outcomes, as well as ways to enhance this combination technique. The combination of these models is a promising technique for improving outcomes for patients with aHCC and warrants further investigation.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited targeted therapies and high recurrence rates. While immune checkpoint inhibitors (ICIs) have shown promise, their efficacy as monotherapy is limited. Clinically, ICIs demonstrate significant benefit primarily when combined with chemotherapy, particularly in the neoadjuvant setting for early-stage TNBC, which yields superior outcomes compared to adjuvant therapy. This review elucidates the tumor immunological principles underlying these observations. We discussed how the suppressive tumor microenvironment (TME), progressive T cell exhaustion, and associated epigenetic scarring constrain ICI monotherapy effectiveness. Crucially, we highlight the immunological advantages of the neoadjuvant approach: the presence of the primary tumor provides abundant antigens, and intact tumor-draining lymph nodes (TDLNs) act as critical sites for ICI-mediated priming and expansion of naïve and precursor exhausted T cells. This robust activation within TDLNs enhances systemic anti-tumor immunity and expands the T cell repertoire, a process less effectively achieved in the adjuvant setting after tumor resection. These mechanisms provide a strong rationale for the improved pathological complete response (pCR) rates and event-free survival observed with neoadjuvant chemoimmunotherapy, as demonstrated in trials like KEYNOTE-522. We further explore the implications for adjuvant therapy decisions based on treatment response, the challenges of ICI resistance, the need for predictive biomarkers, management of immune-related adverse events (irAEs), and future therapeutic directions. Understanding the dynamic interplay between chemotherapy, ICIs, T cells, and the TME, particularly the role of TDLNs in the neoadjuvant context, is essential for optimizing immunotherapy strategies and improving outcomes for patients with TNBC.

Immune-related adverse events (irAEs) are reportedly associated with favorable outcomes in patients with metastatic urothelial carcinoma (mUC) receiving pembrolizumab. Previous studies on this topic focused on the severity of irAEs. The type and number of organs affected by irAEs may also be associated with the therapeutic outcomes.

The present, retrospective study included 146 patients with mUC receiving pembrolizumab between January 2018 and March 2022. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) associated with the type and number of organs affected by irAEs and the severity of the symptoms. IrAEs were graded using the Common Terminology Criteria for Adverse Events version 5.0. The treatment response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Cox proportional hazards was used to assess for any association between the variables and survival. Time-dependent analysis was used to assess the status of irAEs as a prognostic factor.

IrAEs ≥ grade (G) 2 were observed in 48 (33%) patients, of whom 9 (6%) had multiple irAEs. IrAEs ≥G2 were significantly associated with a higher ORR (57% vs. 22% for

CONCLUSIONS

The severity and number of irAEs and the organs affected by them appeared to be relevant to the therapeutic efficacy of pembrolizumab in patients with mUC.

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Lysosome-targeting chimeras represent a promising strategy for degrading extracellular and membrane proteins via the lysosomal pathway, but the available receptor options remain limited. Herein, we report a novel strategy utilizing extracellular heat shock protein 90 (eHSP90) to facilitate lysosomal degradation of target proteins through bifunctional small molecules, termed extracellular heat shock protein 90-targeting chimeras (eHSPTACs). By connecting an HSP90 ligand to a target protein ligand, eHSPTACs effectively induced the internalization and subsequent lysosomal degradation of extracellular Alexa Fluor 488-labeled α-DNP antibody and membrane programmed cell death-ligand 1 (PD-L1). Notably, dPDL1-4 selectively degraded membrane PD-L1 in tumor cells over normal cells, leveraging the elevated expression of eHSP90 in cancer cells. Moreover, dPDL1-4 demonstrated robust in vivo degradation of membrane PD-L1 and significant tumor growth suppression in the B16F10 syngeneic mouse model. Overall, eHSPTACs offer a general platform for tumor-selective degradation of extracellular and membrane proteins, providing a new therapeutic avenue.

Cancer therapy has been revolutionized by immune checkpoint inhibitors (ICIs) that create a new paradigm among cancer immunotherapies. These agents restore the immune system capacity to fight cancer through blocking the action of major immune checkpoint proteins that suppress immune responses such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which tumors exploit for immune escape. Another advancement is the absence of known biomarkers involves ICIs, which can further be translated into new liquid tests like liquid biopsies, indicating the immune status of the patient. Liquid biopsy is a minimally invasive method for identifying tumor-derived components such as circulating tumor cells, cell-free DNA and extracellular vesicles (EVs) from body fluids for analysis. Researchers increasingly use liquid biopsy for biomarkers discovery and patient stratification into clinical applications. Even though immunotherapy has great advances, still there are obstacles faced while using ICIs. Many patients fail to respond to the treatment because of the heterogeneous mechanisms of resistance. Immunotherapy resistance is a dynamic interplay between tumors and their surrounding stroma. To understand this variability, humanized mice models are increasingly used for mirroring human immune responses. Such models offer insight into cancer immunotherapy when human immune system is engrafted into mice, and EV and biomarker profiles are established in those models. EVs reflect differences in tumor characteristics and the immune landscape around tumors to develop personalized strategies to enhance ICI efficacy. This may improve patient prognosis, giving reason to hope for better, more effective treatments.

Immune checkpoint inhibitors (ICI) for cancer treatment can cause inflammatory arthritis (IA). Since ICI-IA has a unique pathogenesis, applying categories of traditional IA may be of limited use.

Participants were ≥18 years old, treated with anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 agents, and had ICI-IA diagnosed by a rheumatologist. We clustered patients using latent class analysis (LCA) applied with phenotypic data from the baseline rheumatology visit. The Bayesian Information Criteria (BIC) was used to select the number of phenotypes. We compared demographics, cancer type and treatments, and IA clinical features and treatments between the estimated phenotypes. Finally, we explored differences in cytokine levels and the presence of shared epitope between the groups.

Twenty variables were used to estimate latent classes. Two distinct phenotypes were indicated by the BIC; 77 patients were estimated to be the first phenotype and 49 in the second phenotype. The statistically significant features that distinguished the phenotypes included higher levels of all components of the CDAI, more stiffness, and more small and upper extremity joint involvement for phenotype 2. Patients in phenotype 2 were marginally more likely to require steroids during their course. There were no significant differences in cancer type, stage or ICI treatment between the phenotype groups. Baseline levels of VEGF-A were higher in phenotype 2.

Two separate phenotypes of ICI-IA were identified using LCA, the second having a more severe polyarthritis at baseline and involving the upper extremities. These subgroups provide an opportunity to identify corresponding biomarkers to predict disease outcomes.

Combining immune checkpoint inhibitors (ICIs) with chemotherapy has significantly transformed cancer treatment, offering better options for esophageal squamous cell carcinoma (ESCC). This comprehensive network meta-analysis evaluates the efficacy and safety of various ICIs in patients with advanced ESCC.

A systematic literature search of randomized controlled trials (RCTs) was performed across major databases up to March 2025, focusing on studies comparing ICIs (as monotherapy or combined with chemotherapy) against chemotherapy alone. Efficacy and safety outcomes were synthesized using a frequentist network meta-analysis model to generate indirect and direct treatment comparisons.

Thirteen trials involving 6997 patients revealed that combining ICIs with chemotherapy generally outperformed chemotherapy alone. Specifically, the combination of toripalimab and chemotherapy demonstrated the most significant improvement in overall survival (HR: 0.58, 95 % CI: 0.43-0.78, p = 0.0003; SUCRA: 0.86). Meanwhile, Sintilimab combined with chemotherapy provided the greatest benefit in progression-free survival (HR = 0.56, 95 % CI [0.46; 0.68], p-value <0.0001; SUCRA: 0.87). Tislelizumab alone was noted for its effectiveness in enhancing overall response rates (RR = 2.08, p = 0.0012). Nivolumab was the most effective in lowering the risk of grade 3 or greater adverse events compared to chemotherapy (RR = 0.28, 95 % CI: 0.21-0.39, p < 0.0001; SUCRA: 1).

Combining ICIs with chemotherapy revealed superior efficacy in advanced or metastatic ESCC compared to chemotherapy alone. These findings support using novel immunotherapeutic agents to enhance patient outcomes, warranting further research to optimize treatment regimens and manage adverse events effectively.

Background/Objectives: Immune-related adverse events (irAEs) triggered by immune checkpoint inhibitor therapy (ICI) have been paradoxically associated with both significant morbidity and improved cancer outcomes. While predictive markers for irAEs have been studied in the PD-1 blockade, less is known for their role in CTLA-4 inhibition. This study aims to fill this gap by evaluating NLR and irAE incidence in a CTLA-4-treated population. Methods: This study is a single-center retrospective cohort study investigating 111 patients treated with CTLA-4 inhibition (ipilimumab) to assess associations for baseline low NLR values with cancer outcomes and irAE type and incidence. Patient charts were manually reviewed by a single physician, and unclear clinical events were assessed by a second physician reviewer. Results: In this cohort, the occurrence of more than one irAE presentation was associated with an improved cancer outcome, OR 1.48 (1.02, 2.15). When stratified by organ-specific manifestation, only endocrinologic irAEs were associated with improved cancer outcome, OR 2.82 (1.19, 6.67). A low baseline NLR was statistically significantly associated with an increased incidence of irAEs of any type, OR 4.34 (1.73, 10.9). Conclusions: These data show that irAE occurrence in cancer patients treated with CTLA-4 inhibition is associated with improved cancer outcomes, similar to that previously seen with PD-1 inhibition. It also suggests that the NLR may serve as a practical peripheral biomarker to predict both cancer response and odds of irAEs in patients treated with CTLA-4 inhibition. This low-cost and widely available tool could provide additional information for modeling cancer outcomes.

Background/Objectives: Immune-related cutaneous adverse events (ircAEs) are common complications of cancer immunotherapy and provide insight into immune-related adverse events (irAEs) more broadly. To enhance our molecular understanding, we characterized ircAEs resulting from single-agent (PD1) and combined immunotherapy regimens (P+C). Clinically, maculopapular rash (MPR) and toxic epidermal necrolysis (TEN) resemble ircAEs, providing a valuable basis for investigations. Methods: To investigate the transcriptome and immune infiltrates in ircAEs, we conducted transcriptomic analyses and multiplexed immunohistochemistry on skin biopsies from patients receiving PD1 and P+C, as well as those with MPR, TEN, and healthy controls. Results: Principal component analysis revealed distinct transcriptomic clustering between ircAEs, MPR, and TEN. Specifically, PD1 ircAEs exhibited a gene expression profile similar to TEN, with upregulation of Type-I-response-related genes (e.g., CXCL9 Log2FC 5.34, p < 0.0001, CXCL10 Log2FC 6.03, p < 0.0001), while P+C ircAEs more closely resembled MPR. Immune infiltrates differed significantly between all groups (p = 0.002 by PERMANOVA for all groups). CD4 T-cells were abundant in the dermis of ircAEs from any type of immunotherapy. However, PD1 stained positive in 1.07% of CD4 cells with PD1 monotherapy, compared to 0.3%, 0.4%, and 0.08% in P+C, MPR, and TEN, respectively. Conclusions: This study identified distinct molecular and cellular signatures in ircAEs depending on the type of immune checkpoint blockade. aPD1-associated ircAEs share similarities with the cytotoxic profile of TEN, while P+C more closely mirrored MPR. These findings support the need for tailored management strategies for ircAEs, emphasizing personalized therapeutic approaches to minimize treatment interruptions while preserving the efficacy of cancer immunotherapy.

To explore the effect of radiotherapy on anti-pd-1 anti-tumor activity in metastatic hepatocellular carcinoma.

Patients with metastatic HCC treated with intensity-modulated radiation therapy (IMRT) in combination with immunotherapy (n = 13) were retrospectively analyzed by comparing its efficacy with that of immunotherapy alone (n = 12) as well as untreated (n = 20) patients with metastatic hepatocellular carcinoma. Animal experiment used mouse hepatocellular carcinoma H22 cell metastatic tumor model and were also divided into a control group, a PD-1 antibody group, an SBRT group, and an SBRT combined with a PD-1 antibody group. SBRT treatment is 8 Gy×3 F. The growth curves of body weight, irradiated tumor (the primary tumor), and non-irradiated tumor (secondary tumor) were plotted for each group of tumor-bearing mice. For this study, we used flow cytometry to examine effector CD8 + T cells expression in both irradiated and non-irradiated tumors, the CD4 + T and CD4+/CD8 + T cells ratio in the spleen, and used enzyme-linked immunosorbent assays (ELISA) to analyze the concentrations of IFN-γ and IL-10 in serum. Tumors were additionally stained with immunohistochemistry Ki-67 and TdT-mediated dUTP nick end labeling (TUNEL). We used hematoxylin-eosin (HE) staining of liver, spleen, lungs, kidneys, and heart to assess the anti-tumor activity of each group of tumor-bearing mice and their tolerance to determine the safety of the approach.

Clinical results: The median survival of IMRT + PD-1 group, PD-1 group, and control group were 17.5 months (95Confidence Interval (CI) 13.2-21.8), 12.5 months (95CI 9.0-16.0), and 5.2 months (95CI 5.5-12.9), respectively (P < 0.001). SBRT combined with PD-1 antibody improved tumor control in both radiated and non-radiated tumors, resulting in a complete cure of the half of mice in animal studies. This was linked to an increased in CD8 + effector T cells infiltration triggered by radiotherapy. HE staining of mice in the SBRT combined with the PD-1 treatment group suggested no damage to the liver, spleen, lungs, kidneys, and heart.

This study showed that SBRT, while being well-tolerated, significantly increased anti-PD-1 antitumor activity by enhancing the tumor immune microenvironment in mice with metastatic hepatocellular carcinoma without significant toxic side effects.

This manuscript was previously submitted as a preprint only in Experimental Hematology & Oncology and has no conflict of interest with this submission.

A 58-year-old female patient with bilateral breast cancer developed unexpected hematochezia at a frequency of approximately 10 episodes per day following adjuvant chemotherapy, with the emergency endoscopy reporting superficial ulcers throughout the entire colon, suggesting a diagnosis of ulcerative colitis (UC). Given the absence of preexisting autoimmune history or detectable autoantibodies, we supposed that the onset of UC was closely related to the chemotherapy. The complex bidirectional relationship between autoimmune rheumatic diseases and cancer continues to be elucidated. Variations in autoimmune disease type, duration, and specific clinical/laboratory features may modulate cancer risk, either increasing or decreasing susceptibility to certain malignancies. These associations could potentially inform type-specific cancer screening strategies. Furthermore, the widespread use of immune checkpoint inhibitors across multiple tumor types, along with their associated inflammatory syndromes, has significant implications for the development and management of autoimmune rheumatic diseases. Herein, we report this case, which could be one of the few bilateral breast cancer cases to be reported with ulcerative colitis, and conducted a literature review of the bidirectional association of breast cancer and autoimmune diseases.

Renal cell carcinoma (RCC) accounts for about 403,000 new cases and 175,000 deaths worldwide each year. Clear cell RCC (ccRCC), the most prevalent subtype, is often driven by genetic mutations, such as VHL inactivation, leading to angiogenesis and immune escape. Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have transformed treatment paradigms, yet therapeutic resistance remains a critical challenge. The immunosuppressive nature of the tumor microenvironment (TME) in ccRCC plays a central role in limiting ICI efficacy. Emerging strategies aim to overcome resistance by targeting key components of the TME, including tumor-associated macrophages, regulatory T cells (Tregs), and cytokine signaling. Agents such as nivolumab, pembrolizumab, and ipilimumab have demonstrated the ability to restore T-cell activity and mitigate immune suppression, offering clinical benefit in metastatic ccRCC. However, response rates vary, highlighting the need for rational combination therapies. ICIs combined with VEGF inhibitors have shown promising outcomes in clinical trials, and novel regimens continue to be explored. Risk stratification and personalized treatment selection are increasingly important as the therapeutic landscape evolves. This review synthesizes current advances in immunotherapy for ccRCC, with a focus on mechanisms of resistance and innovative strategies to enhance immune responsiveness. A deeper understanding of TME modulation and strategic combination approaches is essential to improve survival and quality of life for patients with advanced ccRCC.

Consolidative PD-L1 inhibitors after concurrent chemoradiotherapy (cCRT) have become standard care in locally advanced non-small cell lung cancer (LA-NSCLC). However, the correlation between immune-related adverse event (irAE) characteristics and patient outcomes remains unclear.

This retrospective study enrolled LA-NSCLC patients who received consolidative PD-L1 inhibitors after CRT at four cancer centers. Patients who received CRT alone were also included for comparison. Associations between irAE characteristics, frequency, timing, affected systems, and severity, and progression-free survival (PFS) and overall survival (OS) were assessed. Tumor immune microenvironment (TIME) features were analyzed to identify subpopulations at higher risk of severe irAEs.

Among 107 patients, 59 (55.1%) developed irAEs; 89.8% were grade 1-2 and 10.2% grade 3-4. Patients with irAEs had significantly longer PFS than those without. Late-onset, single-system, endocrine, and mild irAEs predicted better PFS. In contrast, patients with severe irAEs had worse survival than those without ICI consolidation. TIME analysis revealed that severe irAEs were associated with higher CD103+CD8+ T cells infiltration. A > 1.545% cutoff for CD103+CD8+ T cells may help identify patients less likely to benefit from PD-L1 inhibitor consolidation.

Occurrence of irAEs, particularly late-onset, single-system, or grade 1-2 correlated with greater benefit from consolidative PD-L1 inhibitors in LA-NSCLC. Conversely, severe irAEs predict poorer survival, even compared to no ICI consolidation. Elevated CD103+CD8+ T cell infiltration may serve as a biomarker to identify patients at risk of severe irAEs who may not benefit from immunoconsolidation therapy.

While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, they can trigger severe immune-related adverse events (irAEs). The safety and efficacy of ICI retreatment after severe irAEs remain poorly understood.

We conducted a retrospective analysis of 1271 patients with malignancies treated with ICIs at a university hospital in Japan between September 2014 and June 2023. We evaluated the incidence and characteristics of severe irAEs, defined as grade ≥3, and the safety and efficacy of ICI retreatment.

Severe irAEs occurred in 222 patients (17.5%). Patients with single endocrinopathies were excluded, and 46 (28.4%) of the remaining 162 patients underwent ICI retreatment. Upon retreatment, 14 patients (30.4%) experienced recurrent or new grade ≥2 irAEs. One patient who experienced hepatotoxicity (grade 3) at initial ICI treatment developed a recurrence (grade 4). Regarding antitumor response, the objective response rate to retreatment was 28.3% (13/46), with 10.9% achieving complete and 17.4% partial response. The median duration of ICI administration after retreatment was 218 days (95% confidence interval [CI]: 84-399). At 1 year after retreatment, 15.4% (95% CI: 6.8-27.4) of patients discontinued due to irAEs, 44.4% (95% CI: 29.7-58.1) due to disease progression, 6.6% (95% CI: 1.7-16.3) completed planned treatment, and 33.4% (95% CI: 20.3-47.2) continued treatment.

ICI retreatment after severe irAEs demonstrated a manageable safety profile and promising efficacy, even in patients with grade ≥3 irAEs. ICI retreatment may be a viable option for patients with limited alternatives, particularly those showing favorable antitumor responses at initial treatment.

To describe presentation, treatment and outcome of immune checkpoint inhibitor (ICI) associated-vasculitis in cancer patients in a multicentre study.

Thanks to the ImmunoCancer International Registry (ICIR), a multidisciplinary network focused on the research of the immune related adverse events related to cancer immunotherapies, patients presenting with a clinical and/or radiological suspicion of vasculitis and histological evidence of vasculitis after being exposed to ICIs were retrospectively identified.

Twenty-eight cases were identified in the ICIR registry. The median interval between starting ICI treatment and vasculitis diagnosis was 4 months. Small vessel vasculitis was predominant (n = 21), followed by large vessel (n = 4) and medium vessel (n = 3). The small vessel vasculitis included 10 unclassified vasculitis either with limited cutaneous involvement (n = 6) or systemic involvement (n = 4), five IgA vasculitis, three cryoglobulinemic vasculitis, and three ANCA+ vasculitis. At presentation or during the evolution, renal and neurologic manifestations were evidenced in seven cases each (25%). Renal biopsies documented immune glomerulopathies in six cases. Only seven patients (25%) fulfilled the 2022 ACR/EULAR classification criteria (four giant cell arteritis, two EGPA and one GPA). Most patients (90%) required systemic corticosteroid and an additional drug was given in 10 patients (36%). Vasculitis outcome was good: 22 patients had vasculitis complete response, no patient died due to vasculitis. Nine patients (32%) were rechallenged with immunotherapy with only one relapse.

ICI-associated vasculitis are rare, heterogeneous, but can be severe requiring urgent multidisciplinary management with aggressive treatment.

Immune evasion is a hallmark of cancer progression but the role of steroid hormones in this evasion has long been underrated. This oversight is particularly notable for glucocorticoids given that exogenous glucocorticoids remain a cornerstone therapy in various oncological treatment regimens, supportive care and treatment of immune-related adverse events caused by immune-checkpoint inhibitors. Cortisol, the main endogenous glucocorticoid in humans, is secreted by the adrenal cortex in response to stress. Additionally, cortisol and its inactive metabolite cortisone can be interconverted to further modulate tissue-dependent glucocorticoid action. In the past 5 years, intratumoural production of glucocorticoids, by both immune and tumour cells, has been shown to support tumour immune evasion. Here, we summarize current progress at the crossroads of endocrinology and immuno-oncology. We outline the known effects of steroid hormones on different immune cell types with a focus on glucocorticoids and androgens. We conclude with options for pharmaceutical intervention, including the engineering of cell-based therapies that resist the immunosuppressive action of steroid hormones. Overall, local steroid production and metabolism are emerging elements of tumour immune suppression that are potentially amenable to therapeutic intervention. Targeting steroid hormones to enhance anticancer therapies could increase their efficacy but will require expertise in endocrine care.

Immune checkpoint inhibitors (ICIs) have been approved to treat a variety of malignancies, including melanoma, improving the prognosis of these patients. However, they also cause a wide spectrum of rare immune-related adverse events (irAEs), not well-described yet. Although many endocrinopathies have been recognized as irAEs, primary hypoparathyroidism has rarely been reported, and thus clinical suspicion remains low. Herein, we describe the case of a 68-year-old female patient with metastatic melanoma who was admitted to the emergency department with acute symptomatic hypocalcemia due to immune-related (ir)-hypoparathyroidism after 2 cycles of nivolumab/ipilimumab. The patient was treated symptomatically, and her calcium levels were normalized. Parathyroid hormone levels were partially restored during the 6 months of follow-up. A literature review was conducted, summarizing all other subjects who developed ir-hypoparathyroidism after exposure to ICI-based regimen. The review identified 10 additional cases of hypoparathyroidism during immunotherapy. Interestingly, all melanoma cases with ir-hypoparathyroidism had received nivolumab/ipilimumab; 3 of them were also screened and detected with positive calcium-sensing receptor (CaSR) antibodies. Primary hypoparathyroidism may acutely manifest with symptomatic hypocalcemia and care providers should be aware of this rare irAE.

Over the past decade, immunotherapy has revolutionized the treatment algorithm for solid tumors. Immune checkpoint inhibitors (ICIs) demonstrated efficacy against several tumor types, but they can favor the development of immune-related adverse events (irAEs). IrAEs can sometimes be life-threatening. In this review, we will briefly analyze the main gastro-intestinal toxicities and focus on potential strategies for mitigating irAEs, particularly through the modification of gut microbiota (GM) composition. Finally, we will briefly dwell on the potential role of artificial intelligence (AI) in the prediction of irAEs.

Immune checkpoint inhibitors (ICIs) have emerged as a cornerstone of cancer immunotherapy but are associated with immune-mediated adverse events (imAEs), including gastrointestinal toxicities. Among these, enteritis is a less common but clinically significant complication. However, small intestinal involvement remains under-recognized, and endoscopic findings are not well characterized. We report four cases of imAE enteritis in which small-bowel capsule endoscopy (SBCE) was performed. SBCE revealed variable mucosal abnormalities, including villous atrophy, aphthous ulcers, and extensive erosions; in one case, deep circumferential ulcers with stricture were observed. While one patient responded to corticosteroids, the other three required escalation to biologic therapy due to steroid-refractory disease. These findings suggest that SBCE may play a valuable role in assessing disease extent and predicting treatment responsiveness in imAE enteritis. Early utilization of SBCE could facilitate timely therapeutic decision-making in affected patients.

Various endocrinopathies have been described in patients with malignancies who are receiving treatment with immune checkpoint inhibitors (ICIs). We present the case of a patient who was hospitalized with an acute alteration in mental status and was referred to the endocrinology service for evaluation of abnormal thyroid function tests. Subsequent investigation revealed the presence of acute adrenal insufficiency, which was successfully managed with steroid replacement therapy. This case highlights a unique simultaneous presentation of thyrotoxicosis due to thyroiditis and adrenal insufficiency due to hypophysitis in a patient treated with ICI avelumab for 5 months.

Immune checkpoint inhibitors (ICI) were approved by the Food and Drug Administration (FDA) for patients with metastatic renal cell carcinoma (mRCC) in the second- line setting in 2015 and the first-line (1L) in 2018. Little is known about 1 L ICI use in the off-label (before FDA indication-specific approval) and postapproval settings.

We retrospectively analyzed off-label and post-FDA-approval 1 L ICI receipt in a cohort of Medicare beneficiaries ≥66 years old diagnosed with mRCC from 2015 to 2019. Off-label and postapproval 1 L ICI were defined as before or on/after 4/16/2018 (1L ipilimumab/nivolumab approval). Associations between demographic characteristics and 1 L ICI receipt in the off-label and postapproval periods were examined using multivariable logistic regression.

We identified 23,469 patients, of which 368 (2.4%) off-label and 1,663 (21%) postapproval received 1 L ICI. In the off-label period, patients with co-morbid conditions were more likely to receive 1 L ICI compared to patients with no co-morbidities (3+ conditions, OR = 2.00; 95% CL, 1.31-3.05). In the postapproval period, older patients were less likely to receive 1 L ICI (81+ vs. 66-70, OR = 0.60; 95% CL, 0.52-0.69), and patients who were frail were less likely to receive 1 L ICI (OR = 0.77; 95% CL, 0.69-0.87). There were not significant differences in 1 L ICI receipt based on race/ethnicity.

Older patients and patients with more comorbidities were more likely to receive 1 L ICI off-label, but these differences did not persist after FDA approval. After 1 L ipilimumab/nivolumab approval, patients receiving 1 L ICI were more likely younger, healthy, and receiving dual-ICI regimens.

The use of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of many malignancies. However, they may be associated with life-threatening immune-mediated adverse effects.In this article, we present the case of a patient diagnosed with stage IIB acral melanoma (pT4aN0M0) who started adjuvant treatment with pembrolizumab, after which he developed severe myocarditis with myositis and myasthenia gravis overlap syndrome (IM3OS) treated with Efgartigimod.The use of Efgartigimod resulted in a remarkable recovery, marking the first reported acute application of this agent for IM3OS and positive anti-acetylcholine receptor antibodies (anti-AChR).

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.

Immunotherapy has significantly affected cancer treatment and survival rates, accompanied by an increase in immune-related adverse events (irAEs) requiring new management strategies. irAEs can affect various organ systems and have varying severity levels, with higher rates observed when combining immune checkpoint inhibitors. National organizations such as ASCO, the National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society for Medical Oncology have created guidelines for managing irAEs. This chapter expands on these guidelines by discussing practical strategies to improve the multidisciplinary management in irAE care, focusing on the who, what, and how to bridge gaps in care and enhance collaboration between academic and community oncology practices. Effective irAE management involves early recognition and guideline-adherent approaches using a multidisciplinary team, including oncologists, other subspecialists, primary care clinicians, and all care team members. Institutions are developing methods to integrate irAE care into clinical workflows, such as incorporating urgent care clinics and e-consults for efficient irAE management and developing hub-and-spoke models to extend specialized care from academic centers to community hospitals for equitable care delivery. Additionally, effective patient education is critical for improving irAE recognition and health literacy. The new ASCO Community of Practice called the Alliance for Support and Prevention of Immune-Related Adverse Events consortium and patient advocacy group Standing Together to Optimize Research, Interventions, and Education in irAEs initiatives aim to advance irAE clinical care, research, and education through global collaboration, standardized data collection, and improved outreach to patients and caregivers.

Immune checkpoint inhibitors are cancer therapeutics that have shown remarkable success in extending lives in many cancers, including melanoma, MSI-high cancers, and other cancers. However, these therapeutics have not shown benefit for many patients with cancer, especially those with advanced cancer diagnoses. In addition, many patients develop resistance to these therapeutics and/or life-altering adverse events that can include cardiotoxicity, pneumonitis, thyroiditis, pancreatitis, and hepatitis. Extensive efforts to improve cancer care by uncovering mechanisms of resistance to immune therapy in solid tumors have led to identification of new sources of resistance and to the development of new approaches to activate or sustain antitumor immunity. Chronic stimulation of T cells by tumors and by checkpoint inhibitors can lead to a progressive state of T-cell exhaustion. Chronic T-cell activation by the tumor microenvironment (TME) or immune therapeutics can upregulate the expression and function of alternate checkpoints, including the T-cell protein LAG-3. Persistent interferon signaling in the TME can drive epigenetic changes in cancer cells that enable tumors to counter immune activation and disrupt tumor cell elimination. In addition, immune-suppressive macrophages can flood tumors in response to signals from dying tumor cells, further preventing effective immune responses. New clinical developments and/or approvals for therapies that target alternate immune checkpoints, such as the T-cell checkpoint LAG-3; myeloid cell proteins, such as the kinase phosphoinositide 3-kinase gamma isoform; and chronic interferon signaling, such as Jak 1 inhibitors, have been approved for cancer care or shown promise in recent clinical trials.

Immune checkpoint inhibitors (ICIs) significantly prolong the survival of cancer patients. including gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC) patients. Immune-related adverse events (irAEs) are inevitably involved in ICIs treatment sometimes with severe consequences. Extreme caution is necessary for predicting irAEs and precisely screening of appropriate patients. We evaluated the association of interleukin-6 (IL-6) with irAEs and their impacts on ICIs treatment effectiveness in advanced GAC and ESCC patients.

This retrospective study analyzed 121 patients treated with ICIs between March 1, 2020 and August 31, 2023 to evaluate the association between serum IL-6 and ICIs treatment effectiveness. The occurrence of irAEs, including grade and category, and effectiveness of immunotherapy, including objective remission rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), was evaluated. Categorical count data were tested by chi-square test. Nonparametric rank sum tests were performed using Wilcoxon and Kruskal-Wallis test. Survival rate estimation and survival curves were generated using Kaplan-Meier curve and Log-rank test. Univariate and multivariable COX regression analyses were performed to identify independent prognostic factors.

A total of 121 patients including 79 with GAC and 42 with ESCC patients were randomly divided into TC (n=81) and VC (n=40) groups. Higher serum IL-6 levels were associated with increased incidence of irAEs, the outcome analysis also indicated its association with lower DCR, shorter PFS and shorter OS in TC group. The higher IL-6 related irAEs occurrence and poor prognosis (DCR, PFS) was confirmed in the VC group. Individual tumor analysis showed that higher IL-6 was associated with both irAEs occurrence and poor prognosis (DCR, PFS, OS) in ESCC patients, and with irAEs occurrence and poor prognosis (DCR, PFS) in GAC patients. No statistically significant associations were observed between pathological biomarkers including programmed cell death ligand 1 (PD-L1), mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) and either IL-6 levels or irAEs occurrence in both GC and ESCC patients.

Elevated serum IL-6 levels were associated with the incidence of irAEs, and higher IL-6 levels predicted worse prognosis in GAC and ESCC patients with ICIs treatment.

Endometrial cancer (EC) is one of the most common malignancies in women. In recent years, immunotherapy has gradually become a significant treatment option. However, the mechanisms underlying immune checkpoint inhibitor (ICI)-related Adverse Events (AEs) remain poorly understood, posing significant challenges for optimizing clinical treatment strategies. This study aims to integrate the FAERS database and single-cell transcriptomic data to investigate potential mechanisms underlying PD-1 inhibitor-related AEs in EC immunotherapy, with a focus on exploring the PD-1-associated cell communication network and its potential compensatory activation pathways. Data related to AEs were extracted from the FAERS database. Disproportionality analyses, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), were used to quantify signals of immune-related AEs (irAEs) associated with ICIs. We compared the occurrence timing and characteristics of AEs across different drugs. Subsequently, scRNA-seq was performed to analyze the tumor microenvironment of EC, focusing on PD-1-high expressing cell populations. Cell Communication was analyzed and key receptor-ligand pairs were identified. From Q1 2004 to Q3 2024, 21,838,627 drug-related reports were retrieved from FAERS, including 2,202 related to ICIs. ICI-associated irAEs involved 26 organ systems, with general disorders, gastrointestinal disorders, and injury/poisoning as the top System Organ Class (SOC). Fatigue, product use issues, and diarrhea were the most reported Preferred Terms (PTs). PD-1 inhibitors were associated with faster onset of AEs compared to PD-L1 inhibitors and Weibull modeling indicated an early failure-type AE pattern for both treatments. Single-cell analysis further demonstrated that PD-1 was highly expressed in CD8 + cytotoxic T cells and Tfh cells, which communicated with other cells within the tumor microenvironment through key receptor-ligand pairs such as CXCL12-CXCR4 and CXCL16-CXCR6. These findings suggested that PD-1 inhibitors may induce AEs through compensatory activation of the CXCR4 and CXCR6 pathways. This study suggested that PD-1 inhibitors may contribute to irAEs in EC, potentially through compensatory activation of the CXCR4 and CXCR6 pathways. By integrating FAERS and scRNA-seq data, key receptor-ligand interactions were identified, providing preliminary insights that could inform future efforts to optimize immunotherapy efficacy and mitigate AEs. However, further validation through clinical studies and mechanistic research is needed to confirm these findings.

Immune checkpoint inhibitor-related interstitial pneumonia (CIP) poses a diagnostic challenge due to its radiographic similarity to other pneumonias. We developed a non-invasive model using CT imaging to differentiate CIP from other pneumonias (OTP).

We analyzed CIP and OTP patients after the immunotherapy from five medical centers between 2020 and 2023, and randomly divided into training and validation in 7:3. A radiomics model was developed using random forest analysis. A new model was then built by combining independent risk factors for CIP. The models were evaluated using ROC, calibration, and decision curve analysis.

A total of 238 patients with pneumonia following immunotherapy were included, with 116 CIP and 122 OTP. After random allocation, the training cohort included 166 patients, and the validation included 72 patients. A radiomics model composed of 11 radiomic features was established using the random forest method, with an AUC of 0.833 for the training cohort and 0.821 for the validation. Univariate and multivariate logistic regression analysis revealed significant differences in smoking history, radiotherapy history, and radiomics score between CIP and OTP (p < 0.05). A new model was constructed based on these three factors and a nomogram was drawn. This model showed good calibration and net benefit in both the training and validation cohorts, with AUCs of 0.872 and 0.860, respectively.

Using the random forest method of machine learning, we successfully constructed a CT-based radiomics CIP differential diagnostic model that can accurately, non-invasively, and rapidly provide clinicians with etiological support for pneumonia diagnosis.

The tumor environment of prostate cancer (PCa) tissues of high Gleason score has been proved to be more immune suppressive and has higher extracellular matrix (ECM) stiffness, but whether ECM mechanical stiffness is the cause of higher ability of invasiveness and immune escape of PCa with high Gleason score remains uncertain. In this study, we showed that higher polyacrylamide hydrogels (PAAG) stiffness resulted in the progression and immune escape of PCa via integrin β1/FAK/YAP axis. The translocation of YAP into cell nucleus to bind to TEAD2 promoted the transcriptional activation of USP8. NBR1 could be ubiquitinated, and then degraded, via interacting with P62/SQSTM1 and through autophagy-lysosome pathway. Increased expression of USP8 promoted the abundance of NBR1 via K63-linked de-ubiquitination and PD-L1 via K48-linked de-ubiquitination in response to high PAAG stiffness. NBR1-mediated selective autophagy accelerated the degradation of MHC-1 of PCa. The USP8 inhibitor presented a potential application value in sensitizing immunotherapy of PCa. Taken together, we identified a USP8-mediated de-ubiquitination mechanism that involves in the process of high PAAG stiffness-mediated high expression of PD-L1 and low expression of MHC-1 of PCa cells, which provided a rationale of immunotherapy sensitization of PCa via USP8 inhibition.

This study aimed to investigate the safety and efficacy of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) according to different PD-L1 expression statuses in a real-world setting.

This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate.

A total of 409 patients, 65.0% (n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% (n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 109/L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 109/L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs.

A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.