Search Results (842)

Local recurrence after breast cancer surgery presents a critical challenge, demanding novel local immunotherapies capable of eliminating residual disease while avoiding systemic toxicity. In situ-forming hydrogels, functionalized with bioactive cargoes, represent a promising platform for precise spatiotemporal drug delivery directly into the post-resection tumor microenvironment. This review comprehensively examines the core design principles governing these advanced materials, highlighting their biocompatibility, stimuli-responsive behavior, tunable mechanics for conforming to surgical cavity, and capacity for multifunctional integration. A key mechanism discussed is how this controlled release profile orchestrates a temporal progression from innate immune activation to robust adaptive immunity. Despite significant promise, translational success faces substantial hurdles, including efficacy validation, scalable manufacturing, regulatory pathway definition, and the lack of predictive biomarkers. Future research priorities include optimizing drug/antigen release kinetics, establishing standardized characterization methods for complex biohybrid systems, and designing adaptive clinical trials incorporating detailed immunomonitoring. By integrating functional biomaterials with immuno-oncology, in situ-forming hydrogels offer a paradigm-shifting approach for postoperative cancer treatment. This review provides a strategic roadmap to accelerate their translation from bench to bedside. Full article

Neoadjuvant therapy has become the standard of care in early-stage triple-negative breast cancer (TNBC), providing both prognostic information and a platform for treatment individualization. The achievement of a pathological complete response (pCR) is strongly associated with excellent long-term outcomes, whereas the presence of residual disease (RD) indicates a markedly increased risk of recurrence. This dual prognostic value has established post-neoadjuvant treatment as a critical arena for risk-adapted strategies. In patients achieving pCR, de-escalation of adjuvant therapy is under active investigation, with several randomized trials assessing whether surveillance may safely replace prolonged immunotherapy. Conversely, the management of patients with RD has become increasingly complex, as clinicians must navigate between established options such as capecitabine, olaparib, and pembrolizumab, while antibody-drug conjugates are likely to emerge as future therapeutic options in this high-risk setting. In parallel, locoregional approaches are evolving, with trials evaluating axillary de-escalation and even the omission of surgery in highly selected cases. Looking forward, the integration of biomarkers such as circulating tumor DNA and tumor-infiltrating lymphocytes may help refine these strategies, paving the way toward truly personalized post-neoadjuvant care in TNBC. Full article

Anti-PD-1 therapies have transformed cancer treatment by restoring antitumor T cell activity. Despite their broad clinical use, variability in treatment response and immune-related adverse events underscore the need for therapeutic optimization. This article provides an integrative overview of the pharmacokinetics (PKs) of anti-PD-1 antibodies—such as nivolumab, pembrolizumab, and cemiplimab—and examines pharmacokinetic–pharmacodynamic (PK-PD) relationships, highlighting the impact of clearance variability on drug exposure, efficacy, and safety. Baseline clearance and its reduction during therapy, together with interindividual variability, emerge as important dynamic biomarkers with potential applicability across different cancer types for guiding individualized dosing strategies. The review also discusses established biomarkers for anti-PD-1 therapies, including tumor PD-L1 expression and immune cell signatures, and their relevance for patient stratification. The evidence supports a shift from traditional weight-based dosing toward adaptive dosing and therapeutic drug monitoring (TDM), especially in long-term responders and cost-containment contexts. Notably, the inclusion of clearance-based biomarkers—such as baseline clearance and its reduction—into therapeutic models represents a key step toward individualized, dynamic immunotherapy. In conclusion, optimizing anti-PD-1 therapy through PK-PD insights and biomarker integration holds promise for improving outcomes and reducing toxicity. Future research should focus on validating PK-based approaches and developing robust algorithms (machine learning models incorporating clearance, tumor burden, and other validated biomarkers) for tailored cancer treatment. Full article

Tumor mutational burden (TMB) and tumor-infiltrating lymphocytes (TILs) are key biomarkers for predicting immunotherapy responses in cutaneous melanoma. The discordance between brisk TIL morphology and absent cytokine signals complicates immune profiling. We examined the interactions between TMB, TIL patterns, cytokine expression, and genomic alterations to uncover immune escape mechanisms and refine prognostic tools. A structure-based BRAF druggability analysis was performed to anchor the genomic findings in a therapeutic context. Primary cutaneous melanoma cases (N = 205) were classified as brisk (n = 65), non-brisk (n = 60), or absent TILs (n = 80) according to the American association for cancer research (AACR) guidelines. Inter-observer concordance was measured using intraclass correlation. Tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels were graded using immunohistochemistry. Eleven brisk TIL cases lacking TNF-α expression were analyzed using the (Illumina TruSight Oncology 500, Illumina-San Diego, CA, USA). Dabrafenib docking to the BRAF ATP site was performed with Glide SP/XP and rescored with Prime MM-GBSA. Brisk TILs lacking cytokine signals suggested post-translational silencing of TNF-α/IFN-γ. Among the 11 profiled cases, eight exhibited high TMB and copy number alterations, with enrichment of nine metastasis/immune regulation genes. Inter-observer concordance was high (absent TILs, 95%; brisk TILs, 90.7%). BRAF docking yielded a canonical type-I pose and strong ATP pocket engagement (ΔG_bind −84.93 kcal·mol⁻¹). Single biomarkers are insufficient for diagnosis. A multiparametric framework combining histology, cytokine immunohistochemistry (IHC), and genomic profiling enhances stratification and reveals immune escape pathways, with BRAF modeling providing a mechanistic anchor for the targeted therapy. Full article

Immunogenic cell death (ICD) is a specialized form of cell death that triggers antitumor immune responses. In tumors, ICD promotes the release of tumor-associated and tumor-specific antigens, thereby reshaping the immune microenvironment, restoring antitumor immunity, and facilitating tumor eradication. However, the regulatory mechanisms of ICD and its immunological effects vary across tumor types, and a comprehensive understanding remains limited. We systematically analyzed the expression of 34 ICD-related regulatory genes across 33 tumor types. Differential expression at the RNA, copy number variation (CNV), and DNA methylation levels was assessed in relation to clinical features. Associations between patient survival and RNA expression, CNVs, single-nucleotide variations (SNVs), and methylation were evaluated. Patients were stratified into immunological subtypes and further divided into high- and low-risk groups based on optimal prognostic models built using a machine learning framework. We explored the relationships between ICD-related genes and immune cell infiltration, stemness, heterogeneity, immune scores, immune checkpoint and regulatory genes, and subtype-specific expression patterns. Moreover, we examined the influence of immunotherapy and anticancer immune responses, applied three machine learning algorithms to identify prognostic biomarkers, and performed drug prediction and molecular docking analyses to nominate therapeutic targets. ICD-related genes were predominantly overexpressed in ESCA, GBM, KIRC, LGG, PAAD, and STAD. RNA expression of most ICD-related genes was associated with poor prognosis, while DNA methylation of these genes showed significant survival correlations in LGG and UVM. Prognostic models were successfully established for 18 cancer types, revealing intrinsic immune regulatory mechanisms of ICD-related genes. Machine learning identified several key prognostic biomarkers across cancers, among which NT5E emerged as a predictive biomarker in head and neck squamous cell carcinoma (HNSC), mediating tumor–immune interactions through multiple ligand–receptor pairs. This study provides a comprehensive view of ICD-related genes across cancers, identifies NT5E as a potential biomarker in HNSC, and highlights novel targets for predicting immunotherapy response and improving clinical outcomes in cancer patients. Full article

Overcoming immune resistance remains the critical barrier to durable immunotherapy responses. Tumors with non-inflamed, “cold” microenvironments exclude cytotoxic lymphocytes and evade checkpoint blockade. Innate nucleic acid-sensing pathways—including TLRs, RIG-I-like RNA sensors, and the cGAS–STING DNA-sensing axis—can recondition this hostile landscape by licensing dendritic cells, restoring antigen presentation, and recruiting effector T and NK cells. In this review, we synthesize mechanistic insights into how these receptors function across tumor and immune compartments and evaluate recent translational advances spanning small-molecule and nucleic acid agonists, engineered delivery systems, and clinical trials. We highlight challenges that have limited clinical impact, including pathway silencing, systemic toxicity, and lack of predictive biomarkers, while emphasizing emerging solutions such as tumor-intrinsic targeting, CAR-T/NK engineering, and biomarker-guided patient selection. By integrating innate activation into rational combination regimens, innate immune reprogramming offers a blueprint to convert resistant disease into one susceptible to durable immune control. Full article

This review covers issues related to the characteristics, diagnosis, and treatment of colorectal cancer (CRC). It discusses traditional methods of treating colorectal cancer, including surgery, chemotherapy, and radiotherapy, as well as modern approaches, including targeted therapies, immunotherapy, and innovative gene therapy strategies. Particular attention is paid to the identification of molecular subtypes of CRC, which has revolutionized treatment in advanced stages of the disease and contributed to improved patient survival. The role of biomarkers, including liquid biopsy, in diagnosis, therapy monitoring, and treatment response assessment is emphasized. The potential of artificial intelligence in planning and optimizing surgical procedures is also discussed, opening up new possibilities in personalized therapy. This article provides up-to-date knowledge on the molecular mechanisms of CRC, diagnostic prospects, and directions for the development of precision therapies, serving as a valuable source of information for both clinicians involved in the treatment of CRC and patients wishing to deepen their knowledge of the disease and modern therapeutic options. Full article

Background/Objectives: The high prevalence of oral squamous cell carcinoma (OSCC) has driven the development of surgical and oncologic techniques to improve survival. Despite advancements in surgical technique and chemoradiation protocols, survival rates for locally advanced OSCC remain low due to high recurrence and metastasis. This has driven the exploration of neoadjuvant treatment protocols as a potential pathway towards improving organ-preserving resection, de-escalating adjuvant treatment, and improving overall and recurrence-free survival. Methods: This is a narrative review summarizing the current literature and ongoing trials on neoadjuvant treatment for OSCC. PubMed was searched using a snowballing technique to capture all relevant clinical trials. Results: 21 clinical trials were identified. Although neoadjuvant chemotherapy was associated with favorable pathologic outcomes, clinical trials demonstrated variable survival outcomes. In contrast, neoadjuvant immunotherapy for OSCC demonstrated improved pathologic responses and survival outcomes, with a low incidence of grade 3–4 adverse events. Conclusions: Neoadjuvant therapy in OSCC shows promise but does not yet constitute standard of care. Neoadjuvant immunotherapy has encouraging response rates and lower treatment-related toxicities in comparison to neoadjuvant chemotherapy. Although recent clinical trials have presented strong evidence to support the use of neoadjuvant immunotherapy in the treatment of locally advanced OSCC, further randomized trials are required to establish standardized neoadjuvant protocols and biomarkers to assess treatment response. Full article

Background/Objectives: Radiomics is a powerful and emerging tool in oncology, with many potential applications in predicting therapy response and prognosis. To assess the current state of radiomics in melanoma, we conducted a systematic review of its various clinical uses. Methods: We searched three databases: PubMed, Web of Science and Scopus. Each study was classified based on multiple variables, including patient number, metastasis number, therapy, imaging modality, clinical endpoints and analysis methods. The risk of bias in the systematic review was assessed with QUADAS-2, and the certainty of evidence in the meta-analysis with GRADE. Results: Forty studies involving 4673 patients and 24,561 lesions were included in the analysis. Metastatic disease was the most frequently studied clinical setting (85%). Immunotherapy was the most commonly investigated treatment, featured in half of the studies. Computed tomography (CT) was the preferred imaging modality, appearing in 17 studies (42.5%). Radiomic features were most often extracted using three-dimensional (3D) analysis (72.5%). Across 24 studies investigating the prediction of treatment response and survival, only 9 provided sufficient data (Area Under the Curve, AUC, and standard error, SE) for inclusion. A random-effects model estimated a pooled AUC of 0.83 (95% CI: 0.74 to 0.92), indicating strong discriminative performance of the radiomic models included. Low to moderate heterogeneity was observed (I² = 28.6%, p = 0.4741). No evidence of publication bias was detected (p = 0.470). Conclusions: Radiomics is increasingly being explored in the context of melanoma, particularly in advanced disease settings and in relation to immunotherapy. Most studies rely on CT imaging and 3D feature extraction, while molecular integration remains limited. Despite promising findings with strong discriminative performance in predicting therapy response, further prospective, standardized studies with higher methodological rigor are needed to validate radiomic biomarkers and integrate them into clinical decision-making. Full article

Background: Nivolumab plus chemotherapy is a standard first-line treatment for advanced gastric cancer (GC), but reliable early biomarkers for predicting treatment outcomes remain lacking. This study aimed to identify early immunological predictors through dynamic immune profiling. Methods: Fifty patients with advanced or unresectable GC receiving nivolumab plus XELOX or FOLFOX were enrolled. Peripheral blood was collected at baseline, week 1, and week 6. Plasma biomarkers (Granzyme B, Ki-67, CXCL10, IFN-γ, TGF-β1) were measured by ELISA, and immune cell subsets, including cytotoxic T cells, immune checkpoint–positive populations, and memory T-cell subsets, were analyzed by flow cytometry. Cutoffs were defined by medians, established thresholds for NLR and lymphocyte count, and criteria for long-term response (≥9.5 months). Associations with response and progression-free survival (PFS) were evaluated using Kaplan–Meier analysis, Cox regression, and ROC curves. Results: Early responders exhibited significant increases in Granzyme B and CXCL10, with ΔGranzyme B alone and in combination with ΔKi-67 predicting response with high accuracy. A lower week 1 neutrophil-to-lymphocyte ratio was associated with long-term benefit. Elevated week 1 CD8⁺ T-cell proportion and greater decreases in PD1⁺CD69⁺Ki-67⁺CD8⁺ T cells were linked to improved PFS. Higher baseline PD1⁺LAG-3⁺Ki-67⁺CD8⁺ T-cell levels and combined TIM-3⁺/LAG-3⁺ expression enhanced prognostic stratification. Additionally, elevated baseline activated TEMRA cells and declines at week 6 in the same subset correlated with better outcomes. Conclusions: These findings highlight the clinical utility of serial immune monitoring to enable early treatment stratification and guide personalized immunotherapy strategies in advanced GC. Full article

Background: Nitric oxide (NO) is a gaseous free radical produced from L-arginine by the nitric oxide synthase (NOS) enzymes. NO exerts a dose-dependent biphasic effect on lung cancer development, angiogenesis, and dissemination. The widespread contribution of nitric oxide signaling to lung cancer biology has cast a spotlight on the identification of NO-based therapeutic approaches as well as the use of fractional exhaled NO (FeNO) as a prognostic biomarker of clinical control. However, the significance of lung cancer treatment and prognosis has not been fully elucidated. Objective: This narrative review gives an overview of NO in lung cancer, focusing on its therapeutic and prognostic implications. Results: FeNO may help to assess the complications associated with non-pharmacological treatments, including postoperative pneumonia and radiation pneumonitis. By contrast, the role of FeNO dynamics during pharmacological treatment is still largely unexplored due to the suppressive effect of chemotherapy on FeNO levels. The rise of immunotherapy may pave the way to a better evaluation of FeNO as a prognostic biomarker of treatment response. The dichotomous involvement of NO in lung cancer events has led to the adoption of several NO-centered treatments that are focused on both inhibiting and enhancing NO signaling. However, NO chemical and biological characteristics have hindered its implementation in clinical practice. Conclusions: In the coming years, the advancements in drug delivery systems may lead to more effective anti-cancer applications of NO by improving tumor targeting and minimizing the systemic side effects. Together, our findings emphasize the promising role of NO in lung cancer treatment, underscoring the challenges and avenues for future research. Full article

Small Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy representing approximately 15% of all lung cancers. Characterized by rapid progression, early metastasis, and high circulating tumor cell burden, SCLC has a poor prognosis. Although initial responses to chemotherapy, radiotherapy, and immunotherapy are common, relapse due to acquired resistance is nearly inevitable. Molecular studies have identified four transcription factor–driven subtypes—ASCL1, NEUROD1, POU2F3, and YAP1—each with distinct biological traits and therapeutic vulnerabilities. However, clinical classification remains largely homogeneous, limiting precision treatment strategies. Immunotherapy has modestly improved survival, as demonstrated in trials like IMpower133, CASPIAN, and ADRIATIC. Yet only a small subset of patients—approximately 12%—achieve long-term survival beyond five years. Understanding the biological and immunological profiles of these exceptional responders is critical. Future research should prioritize comprehensive biomarker integration, including PD-L1, TMB, DLL3, CD3, and emerging targets. Novel agents such as tarlatamab (DLL3-targeting) and ifinatamab deruxtecan (B7-H3–targeting) have shown encouraging efficacy in early-phase trials, though predictive markers remain elusive. A multi-dimensional approach combining tissue, blood, and immune profiling is essential to advance precision oncology in SCLC and improve patient selection for emerging therapies. Full article

Hepatocellular carcinoma (HCC) management has evolved remarkably with the advent of diverse therapeutic options, particularly systemic and surgical treatments. Combination immunotherapy has redefined the treatment paradigm for advanced HCC and contributed to improved patient outcomes. However, this brings forth challenges such as immune-related adverse events that complicate decision-making. Surgical strategies have expanded with the emergence of conversion therapy and borderline resectability, offering curative potential for a broader patient population. However, robust evidence of their long-term efficacy is lacking. Therefore, decision-making biomarkers have gained prominence across treatment modalities. This review explores the current landscape of predictive, prognostic, and treatment-response biomarkers in HCC, from molecular and immune signatures to radiological and biochemical markers, highlighting their role in optimizing therapeutic strategies. By integrating recent advances in basic and translational research with clinical practice, we aim to outline a biomarker-driven framework for individualized care in HCC. Full article

Background: Immune checkpoint inhibitors (ICIs) have transformed outcomes in advanced cancers; however, the value of continuing treatment after radiologic progression remains uncertain. We systematically assessed the efficacy and safety of ICI continuation beyond progression, focusing on the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Methods: PubMed/MEDLINE, Embase, and the Cochrane Library were searched from inception to 31 March 2025. Eligible reports included retrospective cohorts, prospective trials, post hoc analyses, and pooled regulatory reviews that compared outcomes after ICI continuation versus discontinuation or historical controls. Quality was appraised with the Newcastle–Ottawa Scale (observational designs) and the Cochrane Risk-of-Bias tool (randomized trials). Results: Fifty studies involving 8989 patients met the inclusion criteria: 41 retrospective cohorts; 6 post hoc analyses; 2 randomized trials (1 phase III, 1 phase II); and 1 pooled FDA review. Continuing ICIs beyond progression produced ORRs of 9.3–39% in non-small cell lung cancer (n = 5102), 14–100% in melanoma (n = 669), and 8–33% in renal cell carcinoma (n = 458). Median OS ranged from 8.9 to 18.2 months in lung cancer, 12 to 29.9 months in melanoma, and up to 34.8 months in RCC. Modest but clinically meaningful benefits were reported in colorectal, head-and-neck, gastric, liver, and urothelial tumors. Conclusions: Select patients—particularly those with melanoma, lung cancer, RCC, or gastric cancer—may derive sustained benefit from ICI therapy after radiologic progression. Decisions should incorporate tumor biology, performance status, and emerging biomarkers. Prospective, biomarker-driven trials are needed to define optimal patient selection and the duration of post-progression immunotherapy. Full article

Background: Despite advances in gene-targeted and immunotherapies, many aggressive cancers—including glioblastoma and triple-negative breast cancer—remain refractory to treatment. Mounting evidence implicates metabolic reprogramming, especially dysregulation of glucose and glutamine metabolism, as a core hallmark of tumor progression. Natural compounds with metabolic-modulatory effects have emerged as promising adjuncts in oncology. Research Question and Objectives: This review investigates the following question: How can metabolic-targeted therapies—particularly those modulating the Warburg effect and glutamine metabolism—improve cancer treatment outcomes, and what role do natural compounds play in this strategy? The objectives were to (1) evaluate the therapeutic potential of metabolic interventions targeting glucose and glutamine metabolism, (2) assess natural compounds with metabolic regulatory activity, (3) examine integration of metabolic-targeted therapies with conventional treatments, and (4) identify metabolic vulnerabilities in resistant malignancies. Methods: A qualitative systematic review (QualSR) was conducted following PRISMA guidelines. A total of 87 peer-reviewed studies published between 2000 and 2024 were included. Inclusion criteria required clearly defined mechanistic or clinical endpoints and, for clinical trials, sample sizes ≥ 30. Data extraction focused on tumor response, survival, metabolic modulation, and safety profiles. Results: Curcumin significantly reduced serum TNF-α and IL-6 (both p = 0.001) and improved antioxidant capacity (p = 0.001). EGCG downregulated ERα (p = 0.002) and upregulated tumor suppressors p53 and p21 (p = 0.001, p = 0.02). High-dose intravenous vitamin C combined with chemoradiotherapy yielded a 44.4% pathologic complete response rate in rectal cancer. Berberine suppressed Akt/mTOR signaling and glutamine transporter SLC1A5 across tumor types (q < 10⁻¹⁰). However, poor bioavailability (e.g., EGCG t½ = 3.4 ± 0.3 h) and systemic toxicity limit their standalone clinical application. Conclusions: Metabolic-targeted therapies—particularly natural compounds acting on glucose and glutamine pathways—offer a viable adjunct to standard cancer therapies. Clinical translation will require biomarker-driven patient stratification, improved delivery systems, and combination trials to optimize the therapeutic impact in treatment-resistant cancers. Full article