Search Results (5,039)

Cancer is a leading cause of death in dogs, and incidence rates in dogs exceed those in humans. Current therapeutic options for canine cancer patients remain limited, with most treatments focused on palliative care. Immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies that have transformed cancer therapy and expanded the therapeutic options in humans could offer the same clinical benefit in canine cancer patients. This study details the engineering and functional characterization of mouse and chimeric mouse–canine anti-canine PD-1 (cPD-1) monoclonal antibodies. We demonstrate that anti-cPD-1 antibodies block the interaction between cPD-1 and its ligand cPD-L1, thereby inhibiting this immune signaling pathway. In a proof-of-concept study in seven companion canine cancer patients, intratumoral therapy with the lead anti-cPD-1 antibody (HugPetmab) was safe, well-tolerated, had no observed adverse events, and showed evidence of tumor control in a subset of injected tumors. These findings support the potential of HugPetmab antibody as an immunotherapeutic option for treating canine cancer patients. Full article

Background/Objectives: Liposarcoma represents a heterogeneous group of mesenchymal malignancies with distinct molecular profiles and clinical behaviors. While localized disease is managed with surgical resection, advanced or metastatic liposarcoma poses a significant therapeutic challenge due to limited response to traditional cytotoxic chemotherapy. This review summarizes current evidence-based systemic therapies and highlights recent advances in subtype-driven treatment strategies. Methods: We review key clinical trials supporting the use of anthracycline regimens, trabectedin, eribulin, and nuclear export inhibition with selinexor, as well as emerging targeted approaches directed at MDM2 and CDK4 amplification. In addition, we discuss the evolving role of immunotherapy, including checkpoint inhibitors and engineered T-cell receptor therapies targeting cancer–testis antigens. Results: Integrating molecular biology with therapeutic development, we emphasize the importance of histologic and genomic classification in guiding treatment selection and clinical trial design. Conclusion: Continued progress in biomarker-driven strategies and rational combination therapies is expected to further refine personalized treatment approaches and improve outcomes for patients with advanced liposarcoma. Full article

mRNA vaccines are a relevant approach in cancer immunotherapy, using messenger RNA to induce immune responses against tumor-associated antigens. In this review, BNT111 and BNT122 are compared as representative off-the-shelf and personalized models. BNT111 is a fixed mRNA vaccine that has demonstrated significant antitumor efficacy against shared melanoma antigens, particularly when combined with immune checkpoint inhibitors. It allows a standardized production via in vitro transcription (IVT) in a cell-free system. Conversely, BNT122 is a personalized vaccine designed to match an individual’s tumor mutations by targeting patient-specific neoantigens to elicit more robust immune responses. It has significant suitability in the adjuvant setting to target minimal residual disease. Despite favorable safety and immunogenicity, the effectiveness of these vaccines is influenced by various factors, including tumor heterogeneity, differences in antigen expression, off-target effects on mRNA-LNP distribution, molecular instability, and complex manufacturing constraints. Neither approach can be directly considered as the definitive optimal vaccine. A comprehensive analysis of their strengths and limitations is vital for a balanced and objective future research direction. Collectively, this emphasizes the need for further improvements in vaccine design and strategies, prioritizing high-quality, safe, and accessible treatments for every cancer-based patient and ensuring their successful integration into healthcare. Full article

Renal cell carcinoma (RCC) is a predominant malignancy of the urinary system, with clear cell renal cell carcinoma (ccRCC) representing 75–85% of clinical cases. Since the early stages are often asymptomatic, nearly 30% of patients present with metastases at diagnosis, which significantly complicates the prognosis. The diverse mechanisms and clinical indications of current strategies, despite recent breakthroughs in immunotherapy, pose a major challenge for systematic application. This review employs the cancer-immunity cycle as a framework to evaluate four critical steps: antigen presentation, T-cell activation, reversal of exhaustion, and immune evasion in the tumor microenvironment. We introduce the major immunotherapy strategies in RCC in this cycle and summarize their clinical position. Combining immune checkpoint inhibitors (ICIs) with tyrosine kinase inhibitors (TKI) has redefined the first-line standard for advanced RCC by addressing both T-cell infiltration barriers and functional suppression. Standalone approaches such as tumor vaccines and cytokines in contrast have shown limited efficacy in advanced settings. In this context, we further propose emerging research directions, such as individualized immunotherapy and multi-target blockade, and point out the relevant biomarkers, offering an integrated perspective of the RCC immune landscape and providing insights for both clinical practice and future research. Full article

Background and Objectives: Metastatic renal cell carcinoma (mRCC) remains a lethal disease despite advances with immune checkpoint inhibitors such as nivolumab. However, a substantial proportion of patients exhibit primary resistance or early progression, highlighting the need for reliable and easily accessible prognostic biomarkers. The C-reactive protein–albumin–lymphocyte (CALLY) index is a novel immunonutritional biomarker integrating systemic inflammation, nutritional status, and immune competence. Materials and Methods: In this retrospective single-center study, 91 patients with mRCC treated with nivolumab were analyzed. Patients were stratified into low and high CALLY index groups based on a receiver operating characteristic-derived cut-off (0.322). Survival outcomes were assessed using Kaplan–Meier analysis and Cox regression models. Results: Patients with a low CALLY index demonstrated significantly shorter progression-free survival (4.5 vs. 13.5 months, p < 0.001) and overall survival (9.1 vs. 25.5 months, p = 0.003). Multivariate analysis confirmed the CALLY index as an independent prognostic factor for both progression-free survival (HR: 2.63, p = 0.002) and overall survival (HR: 1.88, p = 0.035). Conclusions: The CALLY index is a simple, cost-effective, and reproducible biomarker that independently predicts survival in nivolumab-treated mRCC. It may serve as a practical tool for risk stratification and personalized treatment planning in the immunotherapy era. Full article

Background: Although immune checkpoint inhibitors (ICIs) have improved survival in advanced melanoma, predicting individual responses remains challenging; thus, practical and inexpensive biomarkers are needed. In this study, we investigated the prognostic value of the neutrophil percentage–albumin ratio (NPAR) in patients with advanced melanoma receiving ICI therapy. Methods: Fifty patients treated in our clinic were included, with a mean age of 53.3 years and 66% being male. Visceral metastases were present in 76% of the cohort. Through conducting Receiver Operating Characteristic (ROC) analysis, we determined an NPAR cut-off value of 1.81, with patients categorized into low (<1.81, n = 27)- and high (≥1.81, n = 23)-NPAR groups. The progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan–Meier and Cox regression analyses. Results: High NPAR (≥1.81) significantly shortened both PFS and OS. In the univariate analysis, high NPAR emerged as a strong risk factor for PFS (HR: 2.68, p = 0.002) and OS (HR: 3.70, p < 0.001), while multivariate analysis confirmed NPAR as an independent negative prognostic factor for PFS (HR: 2.45, p = 0.006) and OS (HR: 2.82, p = 0.003), regardless of clinical variables. Additionally, visceral metastasis was an independent negative predictor of survival. Conclusions: Pre-treatment NPAR levels may be an independent and potential predictor of survival in advanced melanoma patients receiving ICIs. This easily calculable ratio could provide a practical guide for risk stratification. Full article

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy in which radiotherapy plays a uniquely central role compared with other gastrointestinal cancers. Definitive chemoradiotherapy (dCRT) is widely used as a curative treatment; however, a substantial proportion of patients develop residual or recurrent disease, creating a complex clinical scenario that requires tailored salvage strategies. Salvage esophagectomy offers the potential for long-term survival but remains technically demanding and is associated with significant morbidity because of radiation-induced tissue damage. Less invasive local therapies, such as endoscopic submucosal dissection and photodynamic therapy, may provide effective treatment in selected patients, although their indications are limited by tumor characteristics and post-radiation fibrosis. In addition, immune checkpoint inhibitors have demonstrated promising efficacy in advanced ESCC and may represent a potential therapeutic option in the salvage setting. For patients who are not candidates for curative treatment, palliative esophageal stenting remains an important option for symptom relief, although prior radiotherapy may increase the risk of treatment-related complications. Given the diversity of available treatment modalities and their associated risks, a multidisciplinary and individualized treatment approach is essential. Further prospective studies are warranted to optimize treatment algorithms and improve outcomes in patients with ESCC after dCRT. Full article

Introduction: The role of immune checkpoint inhibitors (ICIs) in locally advanced head and neck squamous cell carcinoma (LA HNSCC) remains uncertain, with randomized trials showing inconsistent results in heterogeneous populations. We conducted a systematic review of randomized trials evaluating ICI-based strategies in LA HNSCC, with outcomes stratified by PD-L1 expression, HPV/p16 status, and cisplatin eligibility to identify patient subgroups most likely to benefit from ICIs. Methods: MEDLINE, Cochrane, and EMBASE databases were systematically searched up to 10 January 2026. Randomized controlled trials (RCTs) evaluating ICIs in patients with LA HNSCC were included. The primary outcome was pooled time-to-event efficacy, including event-free survival (EFS), progression-free survival (PFS), and disease-free survival (DFS) as reported across trials. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for PFS with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q test. Random effects model was applied. Results: A total of 3605 patients from seven phase II/III RCTs were included. In the overall population, no significant difference in EFS/PFS/DFS was observed between ICI and standard therapy (HR 0.90; 95% CI: 0.77–1.06; p = 0.20). However, in subgroup analyses stratified by PD-L1 expression, patients with PD-L1-positive tumors demonstrated improved PFS with ICIs compared with control (HR 0.78; 95% CI: 0.67–0.91; p < 0.0001). In contrast, PD-L1-negative tumors demonstrated inferior PFS in the ICIs arm (HR 1.31; 95% CI: 1.02–1.68; p = 0.03). No significant differences in PFS were observed based on HPV or p16 status. A subset analysis of cisplatin-eligible LA HNSCC trials evaluating the addition of ICIs to standard therapy showed a similar pattern. ICI use in PD-L1-positive patients demonstrated significantly improved PFS (HR 0.76; 95% CI: 0.63–0.92; p < 0.0001), while ICI use in PD-L1-negative patients demonstrated decreased PFS (HR 1.28; 95% CI: 0.99–1.66; p = 0.06). In cisplatin-ineligible populations, ICI regimens did not improve PFS compared with cetuximab plus RT. Conclusions: This study showed that although in the overall population there was no significant difference in EFS/PFS/DFS, in the PD-L1-positive subgroup, patients experienced significantly improved PFS with ICIs compared with control, while in the PD-L1-negative subgroup, patients demonstrated inferior PFS in the ICIs arm; these results were mirrored in the cisplatin-eligible subgroup. Full article

Sex differences influence cancer incidence, treatment response, and susceptibility to cardiovascular toxicity. Males exhibit higher rates and poorer outcomes in most non-sex-specific cancers, while females more frequently experience treatment-related adverse events, including cancer therapy-related cardiac dysfunction. Biological factors such as hormonal status, genetic polymorphisms, immune responses, and pharmacokinetics contribute to these disparities. In cardio-oncology, women—particularly premenopausal or with specific genotypes—may be at increased risk for cardiotoxicity after treatment with anthracyclines, immune checkpoint inhibitors or radiotherapy. Clonal hematopoiesis and certain germline genetic variants such as single nucleotide polymorphisms (e.g., RARG rs2229774, HAS3 rs2232228) are emerging as potential sex-informed biomarkers for predicting cardiotoxicity risk. Despite growing evidence, sex remains insufficiently integrated into clinical trials and guideline development in cardio-oncology. This review highlights the importance of sex-specific surveillance, prevention, and multi-omic risk stratification to advance precision cardio-oncology and support better outcomes for patients across the cancer care continuum. Full article

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and the second leading cause of cancer-related mortality worldwide, underscoring the need for the development of more effective and durable therapeutic strategies. A key mechanism of tumor immune evasion involves activation of immune checkpoint pathways through the upregulation of inhibitory ligand expression within the tumor microenvironment, leading to lymphocyte exhaustion and impaired antitumor immunity. Consequently, immune checkpoints have emerged as important targets for immunotherapeutic intervention, with significant advances over the past decade. Nevertheless, despite demonstrated clinical benefits in selected patient subpopulations, the overall therapeutic efficacy of immune checkpoint inhibitors remains limited, particularly in the context of CRC. In this review, we provide a comprehensive overview of currently approved immune checkpoint-based immunotherapies for cancer treatment, with a specific focus on CRC, as well as ongoing clinical trials and evolving trends in this area. Furthermore, we discuss emerging targets and novel therapeutic strategies, with particular emphasis on innovative small-molecule inhibitors as potential alternatives to monoclonal antibody-based approaches. Finally, we outline future perspectives and potential directions for advancing immune checkpoint-targeted therapies in CRC. Full article

Melanoma adjuvant therapy has substantially improved recurrence-free and distant metastasis-free survival in patients with resected high-risk disease, and more recently, these advances have extended to earlier stages. However, important unmet needs remain, including the management of stage IIIA disease, the optimal treatment strategy after relapse on adjuvant therapy, and the identification of biomarkers capable of refining patient selection. This review summarizes recent advances and unresolved questions in the adjuvant and neoadjuvant treatment of melanoma. We discuss novel systemic strategies, including immune checkpoint inhibitor combinations and personalized neoantigen mRNA vaccines, together with the expanding role of neoadjuvant approaches. We also examine prognostic and predictive tools—such as clinicopathologic models, circulating tumor DNA, serum biomarkers, tumor microenvironment features, and gene expression profiling—that may help better define recurrence risk and therapeutic benefit. Current evidence suggests that although modern therapies have changed the natural history of resected melanoma, a substantial proportion of patients are still overtreated or undertreated when treatment decisions are based on stage alone. Future progress will depend on integrating biological risk stratification with clinical staging and optimizing treatment sequencing across adjuvant and neoadjuvant settings. Full article

Immune checkpoint inhibitors (ICIs) have substantially improved outcomes in advanced melanoma but are frequently linked to immune-related adverse events (irAEs). Vitiligo is a common cutaneous irAE and has been consistently associated with improved patient outcome, including prolonged progression-free and overall survival. It also represents significant visual stigma, particularly when the face is involved. Traditional treatment comprises topical steroids, calcineurin inhibitors, laser, and phototherapy which often have insufficient effects. Since 2023, the first approved drug for non-segmental vitiligo (NSV) with facial involvement, the topical Janus kinase inhibitor ruxolitinib, has been available. However, experience with its use in ICI-induced vitiligo remains limited. In this exploratory analysis, three patients who developed facial vitiligo following ICI therapy applied 1.5% ruxolitinib cream to affected facial areas twice daily. After six (two patients), and twelve months (one patient), extensive repigmentation was observed, quantified at 95.7%, 78.9%, and 99.1% using a novel semi-automatic tool. Quality-of-life questionnaires showed mean reductions of 57.6% (Vitiligo DLQI) and 68.2% (Vitiligo-specific Quality of Life) in disease burden. Treatment was associated with substantial repigmentation without observed side effects. Further evaluation in larger, prospective cohorts is warranted to better define treatment effects, clinical applicability, and long-term safety. Full article

Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is the principal physiological inhibitor of tissue-type and urokinase-type plasminogen activators and a central regulator of fibrinolysis. Beyond its canonical hemostatic role, PAI-1 has emerged as a pleiotropic mediator of tissue remodeling, fibrosis, metabolic dysfunction, cancer progression, cellular senescence, and age-associated immune dysregulation. A central argument of this review is that PAI-1 should be understood not only as a downstream biomarker of aging-associated pathology, but also as an active effector linking senescence-associated secretory phenotype (SASP) signaling, chronic low-grade inflammation, impaired immune surveillance, fibrotic extracellular matrix remodeling, and a prothrombotic state. In this framework, PAI-1 may function as an immune-aging checkpoint: a molecular node through which senescent, stromal, malignant, and inflammatory cells reinforce immune evasion and tissue dysfunction. Structure-guided drug discovery has enabled the development of small-molecule PAI-1 inhibitors, including TM5275, TM5441, TM5509, and TM5614. Among these, TM5614 is an orally available investigational compound that has progressed to clinical evaluation. Preclinical studies support anti-thrombotic, anti-fibrotic, anti-inflammatory, anti-senescent, and tumor-microenvironment-modulating effects of PAI-1 inhibition, while early clinical studies have evaluated TM5614 in chronic myeloid leukemia, immune-checkpoint-refractory malignant melanoma, non-small-cell lung cancer, and COVID-19-associated pneumonia. This review summarizes the biology of PAI-1, expands the discussion of immunoaging, reviews representative preclinical and clinical data, compares available PAI-1 inhibitors, and discusses the translational opportunities and safety considerations for TM5614 and related compounds. Full article

Clear cell renal cell carcinoma (ccRCC) is driven by von Hippel-Lindau (VHL) tumor suppressor loss and persistent activation of hypoxia-inducible factors (HIFs), which coordinately regulate angiogenesis, metabolic reprogramming, redox balance, and tumor–immune interactions. Although immune checkpoint inhibitors and vascular endothelial growth factor-targeted therapies have improved outcomes, resistance remains common due to adaptive network plasticity. Selected natural products have been reported to exhibit multitarget regulatory activities that may influence interconnected oncogenic pathways. This review highlights how compounds such as curcumin, resveratrol, quercetin, and epigallocatechin-3-gallate modulate the VHL-HIF axis, disrupt metabolic and redox homeostasis, and influence tumor–immune system interactions in ccRCC. We propose a system-level framework in which natural products enhance therapeutic sensitivity; however, further validation is required for clinical translation. Full article

Focused ultrasound (FUS)-mediated therapies have evolved with the advent of modern ultrasound-guided technology and MRI imaging, moving from their initial use as thermal ablation to a multifunctional platform for thermal and non-thermal ablation, immunomodulation, and targeted drug delivery. This narrative review explores the potential, limitations, and challenges of ablative high-intensity focused ultrasound (HIFU) therapies: HIFU thermal ablation and non-thermal ablation, histotripsy, as well as non-ablative low-intensity focused ultrasound (LIFU) applications in the management of hepatobiliary cancers. HIFU and histotripsy are reviewed as alternative or complementary treatment options in liver tumors, as well as their potential as bridging therapy. Histotripsy is addressed as a theranostic tool, not only by combining ablation with real-time ultrasound imaging guidance, but also by integrating it with sonobiopsy. It facilitates a liquid sonobiopsy of the ablated tumor by releasing intact tumor antigens and damage-associated molecular patterns, leading to potential molecular profiling. LIFU-induced targeted drug delivery (sono-chemotherapy), sonodynamic therapy, radiosensitization, immunomodulation of the immunosuppressive tumor microenvironment (sono-immunotherapy), and the potential to enhance the effect of immune checkpoint inhibitors in these malignancies are discussed. Since FUS-assisted procedures exhibit dual actions through therapeutic functionality associated with intra- and post-procedural ultrasound imaging guidance, they could have value as a theranostic tool in hepatobiliary interventional oncology. Although promising, the available clinical evidence for FUS-mediated therapies in hepatobiliary malignancies consists predominantly of early-stage feasibility studies, retrospective observational cohorts, and non-randomized comparative analyses. Further studies focused on standardized protocols, validation through large-scale, multicenter, prospective randomized clinical trials comparing FUS-based therapies with established treatments, and long-term follow-up of oncological efficacy could define their future role in multimodal oncological strategies. Full article