Search Results (6,487)

Background/Objectives: Immunotherapy has emerged as an important field of research in non-small-cell lung cancer (NSCLC) and has demonstrated promising results in clinical practice. In recent years, multiple studies have been conducted, increasing the amount of available data. Therefore, the aim of this systematic review is to assess the combination of perioperative immunotherapy with chemotherapy compared to chemotherapy only in patients with resectable NSCLC in terms of survival, pathological response, and adverse events. Methods: The clinical databases PubMed, Cochrane Library, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) were systematically searched, up to March 2026. A two-step selection process served as the screening for eligibility, in which the assessment was based on pre-defined inclusion and exclusion criteria. This process was visualized via a PRISMA diagram. For each included study, the risk of bias was assessed with the help of the Cochrane Risk of Bias 2.0 tool and the Newcastle Ottawa Scale. A narrative synthesis was performed due to heterogeneity. Data were extracted into tables. Results: A total of 16 studies, involving 4646 patients in total, met the eligibility criteria, and their data on study population, intervention, comparison, and outcome were extracted into tabular form. Survival and pathological response rates are continuously higher in patients treated with immunochemotherapy. Findings on adverse events differed across the individual studies, though the results indicate an increased risk of treatment-related adverse events (TRAEs) in patients undergoing the combined treatment approach. Discussion/Conclusions: Chemoimmunotherapy leads to superior clinical outcomes in terms of survival and pathological response rates, though the trend towards a higher incidence and severity of TRAEs warrants further research. The interpretation of findings is limited by differences in study characteristics, mechanism of conduct, and endpoints between the individual studies. Full article

Cholangiocarcinoma (CCA) is an aggressive and molecularly heterogeneous malignancy characterized by a profoundly immunosuppressive tumor microenvironment (TME) and historically limited therapeutic options. Recent advances have redefined the treatment paradigm, with phase III trials establishing chemoimmunotherapy as a standard of care and multi-omic profiling elucidating the interplay between tumor genomics, stromal architecture, and immune regulation. Despite these gains, durable clinical benefit remains confined to a minority of patients, reflecting convergent mechanisms of primary and acquired resistance—including immune exclusion, myeloid-dominant suppression, and genotype-driven “cold” tumor states. In this review, we synthesize emerging insights into the immune landscape of CCA, integrating data from single-cell, spatial, and translational studies to define the cellular and molecular circuits governing immune evasion. Beyond canonical biomarkers such as mismatch repair and microsatellite status, we highlight how spatial organization of immunity—in particular, tertiary lymphoid structures, dynamic myeloid and stromal interactions, and pathway-level features—shape immunotherapy responsiveness. We also examine how tumor-intrinsic alterations, including IDH1 mutation, FGFR2 fusions, KRAS activation, and MTAP loss, define distinct immunologic phenotypes with direct implications for immunotherapeutic response and biomarker-driven patient selection. We evaluate the expanding clinical trial landscape of immunotherapy in CCA and more broadly in BTC, including adoptive cell therapies and cancer vaccines. Together, these advances position CCA as a paradigm of how tumor genotype and microenvironment co-evolve to define immunotherapy sensitivity and resistance. Full article

Immune checkpoint inhibitors (ICIs) show promise in cancer but have limited efficacy in ovarian cancer. This study compared combinations of the PD-1/PD-L1 inhibitor with anti-LAG-3, anti-TIM-3, or anti-CTLA-4 to identify the most effective regimen by assessing T-cell CD8/CD4 ratios and cytokine production. T cells isolated from ovarian cancer tissues (mean 3.8 × 10⁸ cells) were stimulated and treated with the PD-1/PD-L1 inhibitor alone or combined with anti-LAG-3, anti-TIM-3, or anti-CTLA-4. Flow cytometry measured CD8/CD4 expression; ELISAs quantified TNF-α, IL-6, and IFN-γ. Anti-PD-1 monotherapy produced no significant change in CD8/CD4 ratio (1.36 ± 0.43 vs. 1.41 ± 0.36) or cytokine levels. Combination therapy with PD-1/PD-L1 inhibitor + anti-CTLA-4 induced the largest increase in CD8/CD4 ratio (3.69 ± 1.33, p < 0.001) compared with PD-1/PD-L1 inhibitor alone; increases were smaller for PD-1/PD-L1 inhibitor + anti-LAG-3 (2.11 ± 0.63, p = 0.009) and PD-1/PD-L1 inhibitor + anti-TIM-3 (1.87 ± 0.48, p = 0.026). TNF-α rose significantly only with PD-1/PD-L1 inhibitor + anti-CTLA-4 (106.69 ± 45.42 pg/mL, p = 0.008), not with PD-1/PD-L1 inhibitor + anti-LAG-3 (72.46 ± 31.79 pg/mL, p = 0.231) or PD-1/PD-L1 inhibitor + anti-TIM-3 (82.06 ± 33.63 pg/mL, p = 0.074). IFN-γ increase was greater with PD-1/PD-L1 inhibitor + anti-CTLA-4 than with PD-1/PD-L1 inhibitor + anti-LAG-3 (p = 0.026). In conclusion, dual PD-1/PD-L1 and CTLA-4 blockade induced concomitant increases in T-cell CD8/CD4 proportions and cytokine levels compared to monotherapy or alternative ICI pairings. These descriptive ex vivo observations offer preliminary evidence of altered immune profiles, highlighting this combination as a candidate for further functional validation. Full article

This study aimed to investigate the expression of immune checkpoint-associated proteins in phyllodes tumors (PTs) and assess their clinicopathologic and prognostic significance. Surgical resection specimens from 200 patients were included, and the expressions of CD24, Siglec-10, CD47, and SIRPα in both the epithelial and stromal components of the tumor were assessed, with ≥1% positivity considered positive. Of 200 cases, 145 were benign, 44 borderline, and 11 malignant. The expressions of CD24, Siglec-10, CD47, and SIRPα in stromal cells increased with tumor grade: CD24 was associated with stromal cellularity, atypia, and mitosis; Siglec-10 with stromal cellularity and atypia; CD47 with stromal atypia and mitosis; and SIRPα with stromal overgrowth and atypia. While expressions of CD24, CD47, and SIRPα were associated with either shorter disease-free survival (DFS) or shorter overall survival, multivariate analysis identified stromal CD24 expression as an independent predictor of shorter DFS. Immune checkpoint-associated proteins, particularly stromal CD24, CD47, and SIRPα, are associated with adverse features and poor outcomes in PTs, implicating potential prognostic and therapeutic relevance. Full article

Background/Objectives: Extramedullary disease (EMD) is an aggressive and treatment-resistant manifestation of multiple myeloma with limited therapeutic options, particularly in heavily pretreated patients. Methods: We conducted a retrospective study to evaluate the efficacy and safety of concurrent immune checkpoint inhibitors (ICIs) and radiation therapy (RT) in patients with EMD treated at Hackensack University Medical Center and John Theurer Cancer Center between January 2016 and May 2025. Patients were included if they had confirmed EMD and received nivolumab or pembrolizumab with concurrent RT. Results: A total of 21 patients were included, representing a high-risk cohort with a median of 6 prior lines of therapy (range 2–13), including 47.6% triple-class refractory and 19.0% penta-refractory disease. The overall response rate (ORR) was 47.6%, with a clinical benefit rate of 57.1%. Despite these responses, median progression-free survival (PFS) and overall survival (OS) were 4 and 12 months, respectively. Notably, two patients achieved complete responses with nivolumab and RT early in their treatment course following cellular therapy and remain disease-free at last follow-up. The combination of ICIs and RT was generally well-tolerated, with manageable immune-related adverse events and no treatment-related deaths. Conclusions: These findings suggest that concurrent ICI and RT may provide a signal of treatment responses in a subset of patients with advanced EMD, although durability remains limited. Further prospective studies are warranted to further define the role of this combination and identify patients most likely to benefit. Full article

Background: Immune checkpoint inhibitors have significantly improved survival in metastatic melanoma. Combination nivolumab plus ipilimumab demonstrated superior efficacy in randomized trials, including CheckMate 067, but data beyond the first-line setting remain limited. This study evaluated real-world outcomes and predictors of response across different lines of therapy, with an exploratory comparison between first- and second-line use. Methods: This retrospective single-center study included patients with metastatic melanoma treated with nivolumab plus ipilimumab as first- or second-line therapy at Moscow City Oncology Hospital No. 62 between September 2015 and October 2023. Eligible patients had histologically confirmed melanoma and received at least one cycle of dual immune checkpoint blockade. Clinical and demographic data were extracted from electronic medical records. The primary endpoints were progression-free survival (PFS) and overall survival (OS); secondary endpoints included objective response rate (ORR) and safety. Survival outcomes were estimated using the Kaplan–Meier method and compared using the log-rank test. Multivariable Cox proportional hazards models adjusted for clinically relevant covariates were applied to evaluate the association between treatment line and survival outcomes. Additional prognostic analyses were performed using backward stepwise multivariable Cox regression. Results: Median follow-up was 18.2 months (IQR, 6.7–30.4). Median PFS in the overall cohort was 7.9 months (95% CI, 4.2–11.5), and median OS was not reached (NR); 5-year OS: 50%. The ORR was 45.8%, including 15.1% complete responses. Median PFS was 9.0 months (95% CI, 5.0–12.9) in first-line and 6.1 months (95% CI, 3.4–8.8) in second-line patients. Median OS was NR in the first-line cohort and was 30.5 months (95% CI: NR) in the second-line cohort. In exploratory analyses, OS did not differ significantly between patients treated in the first-line (n = 141) versus second-line setting (n = 63) (p = 0.848). After adjustment for clinical and demographic characteristics, line of therapy was not associated with OS (HR 0.93; 95% CI, 0.58–1.50; p = 0.762). Immune-related adverse events were associated with longer PFS (HR 0.66; 95% CI, 0.46–0.93), although this may reflect time-dependent bias. Conclusions: Nivolumab plus ipilimumab demonstrated clinically meaningful activity in both first- and second-line settings. Outcomes were numerically lower than in clinical trials, consistent with broader real-world populations. In exploratory analyses, OS did not differ significantly between treatment lines after adjustment for clinical and demographic characteristics. These findings should be interpreted with caution given the retrospective design and potential sources of bias. Full article

Background/Objectives: Immune checkpoints are critical regulatory pathways that maintain peripheral tolerance and prevent autoimmunity. Among these, the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis serves as a major inhibitory pathway that terminates T cell responses. While protein-based checkpoint blockade (ICB) targeting this axis has revolutionized clinical cancer therapy, its clinical efficacy is frequently limited by low response rates, immune-related adverse events (irAEs), and the emergence of adaptive resistance. To break through these bottlenecks, genetic interruption has emerged as a high-precision alternative to modulate the PD-1/PD-L1 pathway at the nucleotide level. Methods: A comprehensive systematic review of literature was performed across major databases (PubMed, Web of Science), with a focus on high quality studies published up to 2026. Results: Direct genomic disruption via CRISPR/Cas9 and post-transcriptional silencing through RNA interference can effectively neutralize inhibitory signaling at its source. Recent advances demonstrate that targeting upstream regulatory nodes—including metabolic checkpoints (e.g., lactate metabolism) and biophysical mechanisms (e.g., liquid–liquid phase separation)—provides superior transcriptional control over PD-L1. Furthermore, engineering CAR-T cells with multiplex gene editing (e.g., TCR/B2M/PD-1 knockout) or localized scFv secretion significantly enhances antitumor potency while reducing systemic toxicity. Innovations in organ-targeted lipid nanoparticles and stimuli-responsive biomimetic carriers further address the delivery barriers in solid tumors. Conclusions: Gene therapy provides a high-precision platform for PD-1/PD-L1 modulation, offering a viable strategy to overcome adaptive resistance. Future clinical application depends on the refinement of safer editing tools, such as base editing, and the standardization of intelligent delivery systems to ensure controllable and scalable cancer immunotherapy. Full article

Honokiol (HNK), a bioactive compound found in Magnolia species, is a promising, multifunctional agent with therapeutic effects on breast cancer (BrCa). Preclinical evidence, including in vitro and in vivo studies, suggests that HNK inhibits essential oncogenic pathways and reduces oxidative stress, inflammation, metabolic reprogramming, and cancer stemness. HNK demonstrates synergistic activity with chemotherapy, endocrine therapy, targeted therapy, and immune checkpoint inhibitors, increasing sensitivity to treatment across models of ER+, PR+, and HER2+ BrCas, as well as triple-negative breast cancers (TNBC). Nanotechnological delivery systems enhance the solubility, bioavailability, and intratumoral accumulation of HNK, increasing its translational capacity. Although clinical data remain very limited, current evidence in humans is insufficient to draw definitive conclusions regarding the safety and efficacy of HNK. This review summarizes mechanistic, preclinical, and emerging clinical data, highlights challenges in formulation and pharmacokinetics, and anticipates future trends in incorporating HNK into multimodal therapy for BrCa. Full article

Head and neck squamous cell carcinoma (HNSCC) remains one of the most aggressive and heterogeneous malignancies worldwide, characterized by high rates of locoregional recurrence, metastatic dissemination, and therapeutic resistance. Angiogenesis plays a central role in tumor progression by supporting vascular remodeling, hypoxia adaptation, invasion, immune evasion, and metastatic spread. In HNSCC, angiogenic activation is regulated through complex interactions involving hypoxia-inducible factors, vascular endothelial growth factor (VEGF) signaling, stromal remodeling, inflammatory pathways, and epigenetic mechanisms within the tumor microenvironment. Recent evidence has also highlighted the role of non-coding RNAs, particularly microRNAs, and exosome-mediated communication in modulating angiogenic and immune-related signaling pathways. Although antiangiogenic therapies, including monoclonal antibodies and tyrosine kinase inhibitors, have demonstrated biological activity in HNSCC, their clinical efficacy remains limited by tumor heterogeneity, adaptive resistance mechanisms, toxicity, and the lack of validated predictive biomarkers. Several emerging therapeutic strategies are under preclinical or early clinical investigation in HNSCC, including miRNA-based approaches, nanoparticle-assisted delivery systems, vascular normalization concepts, and combinations with immune checkpoint inhibitors; however, robust clinical evidence for most of these strategies remains limited, and their translation to routine practice requires further validation. This review provides a comprehensive overview of the molecular mechanisms regulating angiogenesis in HNSCC and critically discusses current and emerging pharmacological strategies targeting these pathways. Particular emphasis is placed on VEGF/VEGFR signaling, the integration of miRNA and exosome biology, resistance mechanisms, and translational perspectives for biomarker-guided personalized therapy. The novelty of this review lies in the systematic integration of miRNA- and exosome-mediated angiogenic regulation, therapeutic resistance pathways, and precision medicine strategies into a unified pharmacological framework, addressing gaps not fully covered by prior reviews focused primarily on VEGF-targeted agents. Full article

Medulloblastoma is one of the most prevalent pediatric brain tumors. Currently, existing therapies for this devastating type of cancer can only prolong survival time with severe side-effects and relapse. These therapies are not curative for almost a third of treated patients, while most survivors are condemned to a poor quality of life. The addition of immune checkpoint inhibitors (ICIs) to immune therapy has given some hope to those suffering from this type of cancer. Although ICIs provide a valuable contribution to immunotherapy, the exploitation of immune checkpoint inhibition within existing therapeutic strategies to cure Medulloblastoma remains understudied. However, the identification of the main molecular subgroups of medulloblastoma is considered one of the success stories of oncology. This advancement in molecular profiling of MB paved the way to subgroup-directed clinical trials, which may lead to efficacious immune-targeted therapy. However, this relatively new development is still hampered by a substantial biological heterogeneity of the disease and the absence of a full understanding of the various mechanisms behind its resistance to existing therapeutic modalities. The inclusion of chimeric antigen receptor (CAR) T and CAR NK cell therapy within various therapeutic strategies and ongoing clinical trials has given fresh hope those suffering from this fatal disease. However, ongoing clinical trials suggest that this highly promising therapy can be impaired by a number of serious limitations, including cytokine release syndrome, Graft-versus-host disease, the scarcity of target antigens, and severe adverse events. Some of the ongoing clinical trials also suggest that CAR NK is less prone to some of these limitations. This review also highlights the contribution of mass spectrometry-based proteomics, and the increasing role of liquid biopsy rather than tissue biopsy. Full article

Melanoma has long represented a unique challenge in oncology. In its early stages, it can often be cured with surgery alone, resulting in excellent survival outcomes. Its biology is complex and heterogeneous, often including mutations such as BRAF and NRAS, which partly explain its high immunogenicity but also its capacity to relapse. For many decades, the standard approach in resectable stage III melanoma was surgery first, followed by adjuvant therapy. In the last decade, the development of immune checkpoint inhibitors created the opportunity to treat patients before surgery. The neoadjuvant approach is based on the hypothesis that treatment of the intact tumor may enhance antitumor immune priming and activation. The first prospective neoadjuvant studies, including OpACIN and OpACIN-neo, showed high pathological response rates with ipilimumab plus nivolumab and introduced pathological response as an early marker of long-term benefit. The PRADO study showed that treatment response could guide the extent of surgery required. The SWOG S1801 trial demonstrated better event-free survival with perioperative pembrolizumab compared to adjuvant therapy alone. Lastly, the phase III NADINA trial showed that neoadjuvant ipilimumab plus nivolumab followed by response-adapted adjuvant therapy significantly improves outcomes. Biomarkers such as PD-L1, IFN-γ signature, tumor mutational burden and imaging (PET scan) appear promising to predict response, but none have been sufficiently validated for routine clinical practice. Full article

Background: Programmed death-1 (PD-1) inhibitors have significantly improved survival outcomes in melanoma; however, questions persist regarding comparative efficacy across regimens and the predictive value of PD-L1 expression as a biomarker. We therefore performed a meta-analysis evaluating outcomes according to PD-L1 expression status using the most recent follow-up data from each study. Methods: A systematic search was conducted in PubMed, Cochrane and ClinicalTrials.gov from 1 January 2010 to 1 April 2025 for phase II and III randomized clinical trials (RCTs) investigating PD-1 inhibitors as monotherapy or combined with other immune checkpoint inhibitors (ICIs) or targeted therapy in the adjuvant/metastatic setting. Pooled estimates were calculated with random-effects models, and risk of bias was assessed using the Cochrane RoB 2 tool. The present meta-analysis was performed following PRISMA guidelines and was registered in PROSPERO (ID: CRD420251090090). Results: Fifteen RCTs including 9979 patients were included. In the overall analysis, PD-1 inhibitors were associated with significantly improved overall survival (OS, HR = 0.75, 95% CI: 0.66–0.86) compared with control treatments. In the unresectable or metastatic setting, progression-free survival (PFS) was also significantly improved (HR = 0.61, 95% CI: 0.49–0.76). Survival benefits were observed in both PD-L1-positive and PD-L1-negative tumors, with improved PFS in PD-L1-positive (HR = 0.63, 95% CI: 0.48–0.83) and PD-L1-negative patients (HR = 0.58, 95% CI: 0.44–0.77), as well as improved OS in PD-L1-positive (HR = 0.69, 95% CI: 0.59–0.80) and PD-L1-negative patients (HR = 0.79, 95% CI: 0.67–0.93), without evidence of effect modification by PD-L1 expression. PD-1 inhibitor-based regimens were not associated with a statistically significant increase in grade 3–4 treatment-related adverse events (RR = 1.13, 95% CI: 0.71–1.79); however, heterogeneity was substantial (I² = 96.0%). Conclusions: PD-1 inhibitor-based therapies significantly improve survival outcomes in advanced melanoma across PD-L1 subgroups. No clear evidence of differential treatment benefit according to PD-L1 expression was observed, suggesting limited utility as a standalone predictive biomarker. Further studies integrating molecular and immune profiling are warranted to optimize individualized treatment selection. Full article

The pituitary gland is an uncommon site of tumor metastasis and is predominantly associated with malignancies of the lung and breast. Metastatic involvement of the pituitary gland in lung cancer (LC) typically indicates advanced disease and is associated with poor prognosis and pituitary insufficiency, which often remains underdiagnosed and significantly affects quality of life and survival. We present four cases of pituitary metastasis (PM) originating from LC, characterized by distinct histological subtypes, variable timing from initial diagnosis, and diverse clinical manifestations. Clinical presentation was heterogeneous: two patients had involvement of both pituitary lobes with multiple pituitary hormone deficiencies, one had anterior lobe involvement with anterior pituitary deficiency following immune checkpoint inhibitor-associated hypophysitis, and one remained asymptomatic. Therapeutic approaches included partial surgical resection followed by radiotherapy in two patients and radiotherapy alone in the other two; all patients continued systemic antineoplastic therapy and received hormone replacement as indicated. Mean overall survival was 7.5 months. PM can occur across all histological subtypes of LC and typically signifies advanced disease with poor prognosis. Early identification and appropriate management of hypopituitarism may improve quality of life and clinical outcomes. Full article

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death worldwide, and first-line systemic treatment has shifted toward immune checkpoint inhibitor (ICI)-based combinations. Response is heterogeneous, and mechanistic interpretation has lagged behind clinical practice, leaving open the question of why some tumors respond while others do not. This review uses the cancer immunity cycle as an HCC-specific scaffold to map where anti-tumor immunity fails—across priming, trafficking, suppressive myeloid or stromal, and metabolic-hypoxic barriers—and interpret combination strategies and resistance through the dominant barrier each tumor presents. ICI monotherapy rescues only specific failure points within the cycle. Combination regimens may be more effective when they are matched to one or more dominant barriers, whereas response may fail when the selected partner addresses only a secondary barrier while the dominant ecological constraint remains intact. Resistance can be similarly organized into tumor cell autonomous, microenvironmental, treatment-induced, and etiology-specific layers, with disease etiology shaping both baseline immune ecology and therapy-context vulnerability. A mechanism-based, biomarker-guided, and etiology-aware framework may help move the field from broad empiricism toward precision immunotherapy, but it should be viewed as a conceptual and translational organizing model that requires prospective testing in biomarker-stratified studies. Full article

Dysregulation of the c-Myc oncogene is a pivotal event in leukemia pathogenesis and therapy resistance. This review synthesizes current evidence, illustrating that c-Myc drives leukemogenesis by enhancing proliferation, inhibiting apoptosis, and upregulating immune checkpoints like PD-L1. Its overexpression is linked to poor treatment outcomes across various leukemia subtypes. Directly targeting c-Myc remains challenging; however, indirect epigenetic modifiers (BET inhibitors), transcriptional disruption (CDK9 inhibitors), and combination therapies emerge as promising strategies to suppress its oncogenic activity and overcome resistance, paving the way for improved clinical management. Full article