Search Results (1,922)

Background/Objectives: Immune checkpoint inhibitors (ICIs) and other systemic therapies can extend the survival of many patients with advanced melanoma, renewing interest in complementary strategies for unresectable or metastatic disease. Therapeutic cancer vaccines represent a possible approach. Recent evidence suggests commercially available mRNA vaccines can sensitize tumors to ICIs, challenging prior assumptions about neoantigen presentation. Despite renewed public interest in personalized cancer vaccine development, the proliferation of narrative and scoping reviews has not been matched by systematic mechanistic synthesis—platforms investigated across the 2010s and 2020s have not been rigorously compared within a single article. Accordingly, this review focuses on major vaccine platforms and proposes a comparative framework for understanding therapeutic melanoma vaccine development and immunologic rationale. Methods: Melanoma vaccine clinical trials listed on ClinicalTrials.gov were identified from 2010 to 2025. Eligible studies were screened and included in a qualitative review evaluating trial characteristics, vaccine platforms, study design, and reported outcomes. Results: There is one active Phase III clinical trial for melanoma vaccines in the US. Key principles of melanoma vaccinology include adjuvant, antigen, and delivery platform selection. From 2010 to 2025, four vaccine candidates advanced to Phase III trials, two provided Phase III results for peer review, one trial is ongoing, and no vaccines have been FDA-approved. Inconsistent reporting of outcomes and a lack of published results limited comparability across studies, precluding formal meta-analysis. Conclusions: Therapeutic melanoma vaccine options remain limited by translational challenges in study design and reporting gaps. This review synthesizes contemporary clinical trial activity and immunologic principles to inform future research. Full article

Background: Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment, but their safety in patients with pre-existing hepatitis B virus (HBV) infection remains uncertain. HBV reactivation is a recognized complication of immunosuppressive cancer therapy, yet evidence supporting routine antiviral prophylaxis during ICI treatment is limited. This study evaluated HBV reactivation and HBV-related outcomes among HBV-positive cancer patients receiving ICIs. Methods: This multicenter retrospective cohort study included adult patients treated with ICIs between January 2017 and December 2022. Patients were grouped according to receipt of antiviral prophylaxis. The primary outcome was HBV reactivation during ICI therapy. Secondary outcomes included hepatic flare, severity, and timing of reactivation, response to antiviral therapy, and factors associated with HBV-related outcomes. Results: A total of 160 patients were included; 68 received antiviral prophylaxis and 92 did not. HBV reactivation occurred in 3 patients (1.9%) and the odd ratio between antiviral prophylaxis and HBV reactivation was wide and imprecise (2.76; 95% CI 0.25–31.05). Hepatic flare occurred in 16 patients (10.0%) and was more frequent in the prophylaxis group than in the no-prophylaxis group (19.1% vs. 3.3%; p = 0.001). Conclusion: In this multicenter retrospective cohort study, the HBV reactivation rate was low and could not determine whether antiviral prophylaxis reduced the risk of reactivation. Hepatic flares were significantly more common among patients who received antiviral prophylaxis, likely reflecting a higher baseline risk of HBV-related complications in this group. A future randomized controlled trial is warranted to guide risk-adapted antiviral prophylaxis and monitoring. Full article

Background and Clinical Significance: The most common cause of liver toxicity with the use of immune checkpoint inhibitors (ICIs) is autoimmune hepatitis. As most patients with prior viral infections such as hepatitis B and hepatitis C were excluded in trials for the use of ICIs, the safety of ICIs in these patients with active or prior treated hepatitis is unknown. With expanded use of these medications in many malignancies, it is important to understand the risk of viral reactivation with these medications. There are only few case series and reports documenting hepatitis B reactivations with the use of ICIs. Case Presentation: We present a middle-aged woman with a history of treated hepatitis B who presented with metastatic gastric cancer. She was treated with two cycles of 5-FU, oxaliplatin and nivolumab followed by maintenance nivolumab. After 14 months of nivolumab, she developed marked transaminitis and was found to have reactivation of hepatitis B. As autoimmune hepatitis was the initial suspicion, the patient was initiated on prednisone 1 mg/kg with no improvement in transaminases. Due to the significant elevation of HBV DNA, she was diagnosed with hepatitis B reactivation. She was initiated on entecavir with normalization of transaminases and improvement in HBV DNA levels. She was successfully rechallenged with nivolumab with no evidence of recurrent transaminitis or worsening HBV DNA levels. Conclusions: There are case series of HBV reactivation with the use of ICIs. We believe that any patients with known history of HBV should get baseline viral titers prior to initiation of ICIs with serial monitoring of DNA levels. Prospective studies to evaluate risk of reactivation may need to be performed for us to get a better understanding of risks of viral reactivation and potential effects it may have on safety and efficacy of ICIs. Full article

Background/Objectives: First-line therapy for advanced gastric cancer (AGC) has evolved from cytotoxic chemotherapy to HER2-targeted and immune checkpoint inhibitor (ICI)-based regimens, yet conversion surgery (CS) outcomes across these strategies remain poorly characterized. We describe CS outcomes and prognostic factors by first-line strategy at a single center. Methods: We retrospectively reviewed 187 patients with AGC who began first-line therapy from 2011, grouped as cytotoxic (CTX, n = 127), HER2-targeted (trastuzumab, n = 21), or ICI (n = 39). CS was defined as resection after response, including an extended oligometastatic definition (n = 74). Overall survival (OS) was measured from chemotherapy initiation, and prognostic factors were assessed by Cox regression. Results: Median OS was 14.8, 18.9, and 20.9 months for CTX, trastuzumab, and ICI, respectively (p = 0.048). CS rates were comparable (41%, 33%, and 38%; p = 0.794). Pathological response was more pronounced after trastuzumab/ICI (grade 3 and ypStage 0/1; both p < 0.001). Among CS cases, R0 resection (hazard ratio [HR] 0.31) and trastuzumab/ICI therapy (HR 0.37) were independent favorable factors, whereas high inflammatory–nutritional indices (NLR, CAR) were independent poor prognostic factors. OS was comparable between oligometastatic and conventional CS (p = 0.324). Conclusions: In this hypothesis-generating study, response depth tracked tumor biology, whereas survival was determined by R0 resection, targeted/ICI therapy, and host inflammatory–nutritional status—two largely dissociable axes informing biology- and host-based selection of CS candidates for prospective testing. Full article

Cancer immunotherapy via targeting immune checkpoint proteins (ICPs) has transformed the treatment of multiple malignancies, offering improved clinical outcomes over conventional therapies. Immune checkpoint inhibitors (ICIs), including FDA-approved monoclonal antibodies against CTLA-4, PD-1, and PD-L1, as well as emerging agents targeting novel ICPs, have demonstrated strong therapeutic efficacy by restoring antitumor immune responses. In parallel, RNA interference (RNAi)-based approaches involving microRNAs (miRNAs) and small interfering RNAs (siRNAs) have emerged as promising alternative strategies for modulating ICP expression at the posttranscriptional level, enabling selective and simultaneous regulation of multiple immune checkpoint pathways. Preclinical and early clinical studies have indicated effective downregulation of target ICP expression and enhanced antitumor immunity across diverse cancer models. Due to the inherent instability of RNA molecules, the development of RNAi therapeutics has been accompanied by advances in delivery platforms. In this review, we discuss the biological functions of established and novel ICPs, along with immunotherapeutics approved by the FDA and under Phase III clinical development. We also provide an overview of the RNAi mechanism of miRNAs and siRNAs, highlight endogenous miRNAs that regulate immune checkpoint pathways, and summarize ICP-targeting RNAi agents and their corresponding delivery systems under preclinical and clinical development. Collectively, these advances underscore the potential of RNAi-based immune checkpoint modulation, complementing existing ICIs and expanding the next generation of cancer immunotherapy. Full article

Immune checkpoint inhibitors have transformed the treatment of multiple malignancies by restoring antitumor T-cell activity. Their clinical identity is therefore that of immune-enhancing therapies. However, the biology of the PD-1/PD-L1 axis is more complex than simple immune inhibition. Human inborn errors of PD-1 or PD-L1 signaling indicate that this pathway contributes to immune homeostasis, tolerance, protection against selected infections, and the development of memory B cells and antibody responses. These observations raise an important translational question: Can prolonged pharmacologic blockade of PD-1 or PD-L1 can, in selected clinical contexts, induce or reveal acquired humoral immune dysfunction? This review synthesizes evidence linking PD-1/PD-L1 disruption to altered class-switched memory B-cell biology, antibody responses, vaccine immunogenicity, infection susceptibility, and secondary antibody deficiency. It also incorporates emerging evidence that checkpoint blockade may expand age-associated B cells, a population associated with impaired neutralizing antibody responses after vaccination, and counterbalances evidence that vaccination during ICI therapy may enhance antitumor immunity and survival. Current clinical evidence does not establish the incidence, prevalence, reversibility, dose dependence, or causality of an ICI-induced antibody-deficiency syndrome. Instead, the available data support a hypothesis-generating model of heterogeneous humoral remodeling, ranging from preserved or enhanced vaccine-associated immune activation to qualitative antibody failure and secondary antibody deficiency in susceptible patients. Future studies should incorporate baseline and longitudinal measurements of immunoglobulins, vaccine-specific and neutralizing antibodies, class-switched memory B cells, age-associated B cells, plasmablasts, infection burden, and exposure to immunosuppressive treatment. Full article

Head and neck squamous cell carcinoma (HNSCC) remains a significant global health burden with limited survival improvement in locally advanced disease despite multimodal therapy. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have demonstrated substantial clinical benefit in recurrent or metastatic HNSCC, establishing PD-1 blockade as a standard of care. Similar approaches in locally advanced disease, including concurrent administration with chemoradiotherapy or use in the adjuvant setting, have not demonstrated improvement in survival outcomes across multiple randomized trials. Perioperative strategies incorporating neoadjuvant and adjuvant checkpoint inhibition have shown improved event-free and disease-free survival in resectable disease. Meta-analyses of concurrent and adjuvant approaches confirm limited benefit in unselected populations, with modest improvements restricted to biologically defined subgroups. Trial outcomes across disease settings demonstrate a consistent pattern in which therapeutic efficacy varies despite the use of similar agents. Rather than simply summarizing these clinical findings, this review integrates evidence across recurrent/metatstatic, unresected locally advanced and perioperative disease settings into a biologically focused framework to help explain the varying efficacies of immune checkpoint inhibition in HNSCC. Current evidence indicates that the effectiveness of immunotherapy in HNSCC is determined by the biologic context of treatment, including tumor antigen availability, host immune competence, and timing of immune activation. Administration of checkpoint blockade in the presence of intact tumor antigen and preserved immune function is associated with improved outcomes, whereas treatment delivered during or after cytotoxic therapy is limited by lymphopenia and reduced antigen exposure. By synthesizing randomized clinical evidence through this biologic framework, the review provides a conceptual perspective that may help explain previous trial outcomes and inform future biomarker-driven patient selection and treatment sequencing. Optimization of immunotherapy in HNSCC will depend on the integration of immune activation with disease context rather than an escalation of therapeutic intensity. Full article

Immune checkpoint inhibitor-related pneumonitis (CIP) is an uncommon but clinically relevant toxicity in renal cell carcinoma (RCC), where immune checkpoint inhibitors are frequently used either as dual immunotherapy or in combination with VEGF-targeted tyrosine kinase inhibitors. In RCC, CIP poses specific diagnostic challenges because respiratory symptoms and computed tomography findings may overlap with pulmonary metastases, infections, thromboembolic events, heart failure, and TKI-related lung toxicity. This review summarizes the incidence of CIP across pivotal RCC trials and real-world cohorts, compares its epidemiology with non-small cell lung cancer, and discusses clinical presentation, radiological patterns, differential diagnosis, and current management strategies. Particular attention is given to RCC-specific mechanisms, including immune-mediated alveolar injury, T cell activation, cytokine dysregulation, macrophage activation, GSDME-mediated pyroptosis, and the potential contribution of VEGF pathway inhibition to pulmonary inflammation. We also review risk factors, steroid-refractory disease, second-line immunosuppression, and the unresolved issue of ICI rechallenge after pneumonitis. A better understanding of these mechanisms and clinical features may improve early recognition, guide multidisciplinary management, and support safer use of immunotherapy-based combinations in patients with RCC. Full article

Hepatocellular carcinoma (HCC) arises predominantly in chronic liver disease with a uniquely tolerogenic microenvironment. Immune checkpoint inhibitors (ICIs) have improved the prognosis of advanced HCC, yet most patients exhibit low response rates or therapeutic resistance due to the highly immunosuppressive tumor microenvironment. Metabolic reprogramming is not only a core hallmark of HCC but also a key regulatory axis connecting tumor cells and the immune system. HCC cells exhibit pronounced Warburg glycolysis, upregulated glutaminolysis, aberrant lipid storage and oxidation, enhanced ketone metabolism, and altered polyamine flux. These metabolic alterations lead to nutrient competition, lactate accumulation, amino acid depletion, and oncometabolite signaling, resulting in T cell exhaustion, macrophage polarization, T cell expansion, and impaired dendritic cell function, thereby influencing tumor progression, immune escape, and therapeutic resistance. Targeting metabolic–immune crosstalk represents a promising strategy for reversing immunosuppression and enhancing the efficacy of immunotherapy. In this review, we systematically summarize the core patterns of metabolic reprogramming in HCC, dissect the molecular mechanisms of metabolic crosstalk at the tumor–immune interface, and discuss the role of immunometabolic remodeling in therapeutic resistance. This review aims to provide a comprehensive theoretical basis and new research directions for improving the efficacy of HCC treatment by targeting the metabolic–immune regulatory axis. Full article

Immune checkpoint inhibitors (ICIs) have translated the scope of cancer therapy, but their immune-restorative mechanism can lead to immune-related adverse events (irAEs), which can affect several organs with varying severity. Early identification of patients at risk of irAEs is prudent to inform clinical decisions in precision oncology and remains a challenge as current clinical and biomarker methods still lack predictive accuracy. Artificial Intelligence (AI) presents a promising strategy for improving early detection, risk stratification as well as monitoring of irAEs. This narrative review summarizes the current AI modalities for detecting and predicting irAEs risk occurring with ICI therapy, including clinical Machine Learning models, radiomics-based approaches, natural language processing (NLP) systems and the integration of modalities with multimodal AI frameworks. Clinical Machine Learning models demonstrate moderate predictive performance whereas radiomics-derived modeling appears promising for pneumonitis. NLP and language models have achieved higher accuracy for retrospective irAEs detection. Multimodal AI applications offer theoretical potential through diverse data integration that captures the complex biology of irAEs; however, current evidence is limited. All these modalities face limitations of inadequate sample sizes, retrospective design, heterogeneous outcome definitions, class imbalance, and insufficient external validation. AI-based models have significant potential for personalized immunotherapy monitoring but require prospective multicenter validation, standardized datasets and clinically interpretable frameworks prior to implementation. Future advances in multimodal modeling can also enable precise prediction and early detection of irAEs, ultimately improving the safety and effectiveness of cancer immunotherapy. Full article

Background/Objectives: Acute interstitial nephritis (AIN) is a cause of acute kidney injury (AKI) during immune checkpoint inhibitor (ICI) therapy, but biopsy-confirmed data are limited. We estimated institutional proportions of biopsy-confirmed AIN clinically attributed to ICI exposure (ICI-AIN) and characterized its presentation, pathology, treatment, and renal outcomes. Methods: We retrospectively reviewed native renal biopsies performed at Attikon University Hospital from February 2021 through December 2025. Cases were included when ICI exposure preceded AKI and the treating nephrology team documented clinicopathologic attribution to ICI exposure. Results: AIN was identified in 15 of 339 native renal biopsies; 12 cases were attributed to ICI exposure, representing 3.5% of native renal biopsies and 0.8% of 1472 unique ICI-treated patients. Median serum creatinine increased from 1.05 mg/dL at baseline to 3.50 mg/dL at biopsy assessment. During the AKI episode, 10 patients (83.3%) met Kidney Disease: Improving Global Outcomes (KDIGO) criteria for stage 3 AKI. All patients had pyuria, negative urine cultures, and subnephrotic proteinuria. Hematuria and peripheral eosinophilia occurred in four and two patients, respectively. All patients received corticosteroids, and none required kidney replacement therapy. Complete, partial, and absent recovery occurred in eight, two, and two patients, respectively; under the stricter baseline-relative definition, the corresponding numbers were five, five, and two. Conclusions: Biopsy-confirmed ICI-AIN was infrequently detected. Severe AKI was common, urinary findings were nonspecific, and residual renal dysfunction frequently persisted after corticosteroid treatment. Full article

Urothelial carcinoma (UC) is a biologically and clinically heterogeneous disease arising from the bladder and upper urinary tract. Immune checkpoint inhibitors (ICIs) have transformed treatment of advanced UC, yet durable responses remain limited to a minority of patients, underscoring the need to better understand the tumor immune microenvironment (TME). This narrative review examines the UC immune phenotype across disease stages and anatomical sites, integrating evidence from bulk and single-cell transcriptomics, spatial profiling, and translational studies. We describe the principal immune cell populations of the UC TME—including cytotoxic and regulatory T cells, macrophages, myeloid-derived suppressor cells, natural killer cells, B cells, and dendritic cells—and their relationship to established molecular subtypes. We review how this immune landscape evolves from non-muscle-invasive to metastatic disease, including the distinct contexture of upper tract UC and variant histology. We critically evaluate established ICI biomarkers (PD-L1, FGFR3, tumor mutational burden, mismatch repair deficiency) alongside emerging candidates—tumor-infiltrating lymphocyte density, HLA class I expression, tertiary lymphoid structures, and multiparameter transcriptomic scores—noting that most remain investigational and require prospective validation before clinical use. Finally, we address key biological, technical, and clinical barriers to this research and outline future directions in AI-assisted digital pathology and multimodal biomarker integration. A comprehensive characterization of UC immune phenotype is essential to guide rational, biomarker-driven patient selection and optimize next-generation immunotherapy strategies. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of advanced malignancies. However, only a subset of patients respond to treatment. Recent efforts have focused on the identification of novel biomarkers that capture the dynamic and functional state of the tumour immune microenvironment, yet their clinical translation has remained challenging. Methods: To address these limitations, we applied amplified FRET-FLIM (QF-Pro^®) technology to spatially resolve and quantitatively assess functional immune checkpoint interactions directly in cells and FFPE tissue and tumour samples. Results: Using this approach, we demonstrated that PD-1/PD-L1, CTLA-4/CD80, TIGIT/CD155, and LAG-3/MHC-II interactions can be robustly quantified in routine FFPE patient samples from multiple tumour types. Furthermore, in a proof-of-concept study in a melanoma cohort treated with immune checkpoint inhibitors (ICIs) targeting PD-1 or CTLA-4, co-analysis of all four immune checkpoints suggested patterns of concomitant engagement. Notably, patients with high PD-1/PD-L1 interaction levels tended to also exhibit elevated CTLA-4/CD80 interactions. Survival analysis further showed that high LAG-3/MHC-II interaction status was associated with a trend toward improved overall survival even when corrected for tumour stage, irrespective of the specific ICI regimen administered. Conclusions: Although prospective validation in larger independent cohorts would be critical to establish clinical relevance, these findings support the exploration of LAG-3 engagement as a potential biomarker in melanoma immunotherapy, and more broadly highlight immune checkpoint interaction profiling as a promising avenue to examine in patient stratification. Full article

Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in metastatic non-small cell lung cancer (NSCLC), yet only a subset of patients derives durable benefit, suggesting that host and tumor-related factors may modify treatment efficacy. The renin–angiotensin system has been implicated in regulation of the tumor microenvironment, and angiotensin-converting enzyme inhibitors (ACEIs) have therefore been proposed as potential modulators of immunotherapy response. Material and methods: We conducted a retrospective observational cohort study including patients with advanced metastatic NSCLC treated in the first-line setting with treatment-based immunotherapy, with or without chemotherapy, between January 2017 and September 2025. Chronic ACEI exposure was defined as continuous use for at least two years prior to initiation of immunotherapy. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier estimates and compared using the log-rank test, and multivariable Cox proportional hazards models were adjusted. Results: Among 446 eligible patients, 71 (16%) received ACEIs and 375 (84%) did not. The median age of the cohort was 67.5 years, and 70% were male. Adenocarcinoma was the predominant histology (67.7%), and most patients received chemo–immunotherapy (81.6%), while 18.4% received immunotherapy alone. PD-L1 expression ≥ 1% was present in 59.2% of patients. In the overall cohort, median PFS and OS were 12 and 15 months, respectively. Median OS was 17 months in the ACEI group compared with 14 months in the non-ACEI group (log-rank p < 0.047), while median PFS was 14 months versus 11 months, respectively (p = 0.066). The survival advantage was more pronounced for OS than for PFS and remained consistent after adjustment for clinical characteristics including age, sex, ECOG performance status, smoking status, histology, treatment regimen, and PD-L1 expression. Conclusions: These findings suggest that chronic ACE inhibitor use may be associated with improved outcomes in metastatic NSCLC patients treated with immune checkpoint inhibitors. Full article

Immune checkpoint inhibitors (ICIs) are now being introduced into perioperative treatment for several solid tumors. This strategy is usually explained by tumor reduction before surgery or by the elimination of minimal residual disease (MRD) after surgery. However, these explanations may not be sufficient to understand why the timing of ICI treatment, especially before lymph node (LN) removal, is important. In this review, we discuss tumor-draining lymph nodes (tdLNs) from two different aspects. tdLNs are anatomical routes for regional and distant metastasis, but they are also sites where tumor antigens are presented and tumor-specific T cell responses are generated. In particular, preclinical and translational studies suggest that tdLNs may maintain stem-like or progenitor-exhausted T cells (TPEX) that can respond to PD-1 blockade and supply more differentiated exhausted T cells to tumor sites. However, current clinical trials of perioperative ICIs demonstrate therapeutic benefit in specific diseases and regimens, but do not directly establish tdLN preservation or tdLN-resident TPEX maintenance as the decisive mechanism of efficacy. We therefore present the tdLN-reservoir model as a hypothesis-generating framework rather than as a clinically validated basis for modifying lymph node management. We also discuss the possible roles of neoadjuvant and adjuvant ICI in relation to antigen flow, minimal residual disease, metastatic-site draining LNs, postoperative lymphatic dysfunction, and future immune-guided clinical trials. Importantly, current evidence does not support altering standard lymph node surgery or radiotherapy solely to preserve putative tdLN immune-reservoir function. Full article