Search Results (8,268)

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

With colorectal cancer (CRC) accounting for over 1.9 million new cases and 930,000 deaths globally in 2020, there is a critical need for innovative indicators to forecast disease advancement and therapeutic outcomes. The gut microbiome has emerged as a fertile area for discovering such diagnostic and prognostic signals. This narrative review collected current evidence on intestinal microorganisms and their metabolic products as candidate markers for CRC control. Intestinal communities influence malignancy through diverse mechanisms, including metabolic shifts, immune modulation, inflammation, proliferation/apoptosis regulation, genotoxicity, and mucosal barrier disruption. Pathogenic species, such as Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, facilitate tumorigenesis via FadA-mediated signaling and Th17/IL-17 responses. In contrast, beneficial taxa like Faecalibacterium prausnitzii and Akkermansia muciniphila provide protective effects through short chain fatty acid production. Macrophage phenotype physiological equilibrium is altered and inflammatory status fluctuates under the former. Metabolically, hydrogen sulfide damages mitochondrial DNA and secondary bile acids stimulate cellular proliferation. While 16S rRNA sequencing and shotgun metagenomics are established detection strategies, innovative platforms like organoids and gene arrays remain in the exploratory stage. Clinical data indicates that F. nucleatum aligns with advanced tumor stage, and its combined detection with colibactin-producing E. coli achieves high sensitivity for early-stage screening. Additionally, A. muciniphila levels can anticipate the efficacy of PD-1 blockade immunotherapy. Microbiota-derived tools represent a transformative direction in oncology. Future research must focus on standardizing protocols and validating multi-marker panels to enhance clinical translation. Full article

Radiation plays an important role in the treatment of many solid tumors. While conventional fractionation schedules are commonly used, technological advances have allowed safer and more effective dose escalation in the treatment of both primary as well as metastatic lesions. There is growing evidence about the intricate role played by the immune system in modulating the effect of cancer treatment, and several pre-clinical and clinical studies have explored the use of immunotherapy in the treatment of various cancers, both in the metastatic and upfront treatment setting. This approach has shown significant success in the management of melanomas and lung cancers and has prompted exploration of the same strategy in many other cancer subtypes. Radiation has been proposed to synergize the effect of immunotherapy through various mechanisms and is currently being evaluated in various ongoing clinical trials. Several mature clinical studies have also shown significant benefit with the combination and have led to its uptake in routine clinical practice. Furthermore, the use of hypo-fractionated high-dose radiation or Stereotactic Body Radiation Treatment (SBRT) regimens have shown benefits over conventional radiation in this context and are being actively explored as a treatment strategy. Full article

Lung cancer is one of the most common cancers worldwide, with non-small-cell lung cancer (NSCLC) being the most prevalent type. While surgical resection followed by adjuvant platinum-based chemotherapy has been the standard for curative-intent therapy for clinical stage II NSCLC since 2005, disappointing 5-year survival prompted the exploration of newer systemic therapies. In recent years, several landmark trials increasingly support the use of immunotherapy and molecular targeted treatments. The evidence for neoadjuvant chemoimmunotherapy is exciting, but the transition from a surgery-first approach to a new standard of care carries important challenges, including increased surgical attrition, intraoperative technical difficulty, and delays in care. This article provides a comprehensive review of the optimal treatments and emerging therapies for resectable stage II NSCLC. By systematically analyzing recent advances and challenges in NSCLC treatment strategies, we aim to highlight a paradigm shift toward a more molecularly guided, individualized treatment sequence in stage II NSCLC care, with the goal of maximizing each patient’s curative potential. Full article

Cancer vaccines represent a promising strategy in cancer immunotherapy by inducing tumour-specific immune responses. However, their clinical efficacy remains limited due to challenges in antigen selection, including the distinction between self and non-self-antigens, as well as issues related to antigen delivery, immune activation, and tumour immune evasion. Advances in nanotechnology have introduced innovative approaches to improve vaccine stability, targeted delivery, and immunogenicity. Nanoparticle-based platforms, including lipid, polymeric, inorganic nanoparticles, and virus-like particles, enable efficient delivery of tumour antigens and immunostimulatory adjuvants to antigen-presenting cells, thereby enhancing adaptive immune responses. Despite these advances, several translational challenges persist, including immunosuppressive tumour microenvironments, inefficient lymph node targeting, safety concerns, and manufacturing limitations. This review summarizes key nanoparticle platforms used in cancer vaccine development and discusses major barriers to their clinical translation. We also emphasize platform-selection criteria, cargo-dependent carrier design, nanoparticle size constraints, engineering strategies used to improve cytosolic delivery and endosomal escape, and the current clinical pipeline of cancer nanovaccines. Additionally, emerging strategies such as personalized nanovaccines, mRNA vaccine platforms, and combination immunotherapies are highlighted as promising approaches to improve therapeutic efficacy. These advances are expected to accelerate the clinical translation of nanotechnology-enabled cancer vaccines and support the development of next-generation cancer immunotherapies. 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

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, increasingly driven by metabolic dysfunction-associated steatotic liver disease alongside viral and alcohol-related cirrhosis. The tolerogenic immune environment of the liver enables tumor immune escape, with regulatory T cells (Tregs) playing a central role. This review synthesizes human-focused evidence (tissues, blood, clinical cohorts, and single-cell/spatial studies) through September 2025 to define how Tregs are recruited, maintained, and functionally deployed in HCC. Across datasets, intratumoral effector-like Tregs (eTregs) expressing ICOS, CTLA-4, CCR8, and CD39/CD73 accumulate within tumors and co-localize with exhausted cytotoxic PD-1^hi CD8⁺ T cells and suppressive myeloid cells. Recruitment is driven mainly by CCL20–CCR6 and CCL22/CCL17–CCR4 signaling, while CCR8 marks highly suppressive tumor-resident Tregs. Their persistence is supported by TGF-β, IL-10, IL-35, adenosine signaling, IL-2 sequestration, and metabolic adaptation. Spatial biomarkers, including ICOS⁺/CCR8⁺ eTreg density and CD8:Treg ratios, associate with prognosis and emerging immunotherapy responses. Etiology further shapes immune architecture: HBV-related HCC often forms Treg-exhausted T-cell niches around viral antigens, whereas MASLD/MASH promotes stromal and metabolic barriers that may reduce PD-(L)1 efficacy. Current treatments (PD-(L)1 blockade with anti-VEGF or CTLA-4, and some TKIs) intersect with Treg biology, while emerging strategies targeting CCR8, CCR4, ICOS, or the adenosine pathway aim to selectively disrupt intratumoral eTreg networks. This review underscores that an etiology-aware, spatial-biomarker framework may guide the integration of selective Treg targeting with PD-(L)1-based therapies in HCC. Full article

Endometrial carcinoma (EC) is now classified primarily by molecular subtype—POLE-ultramutated, mismatch repair–deficient (dMMR), TP53-mutant/copy-number-high (CNH), and “no specific molecular profile” (NSMP)—a framework that has reshaped prognostic counseling and adjuvant therapy decisions. Yet several practically important questions remain insufficiently addressed in real-world cohorts: whether all four mismatch repair genes confer an equivalent favorable prognosis, whether all POLE alterations carry the same survival benefit or only specific pathogenic variants, and whether molecular subtypes retain prognostic value after adjustment for histology and tumor burden. We aimed to address these questions in 2901 patients pooled from the MSK-IMPACT 50K Clinical Sequencing Cohort (n = 2372; discovery) and the TCGA UCEC PanCancer Atlas (n = 529; validation)—the largest dual-cohort genomic analysis of EC reported to date. Across both cohorts, all four MMR gene–mutant subgroups (MLH1, MSH2, MSH6, PMS2) conferred equivalently favorable overall survival (OS) (six-group log-rank p = 7.66 × 10⁻¹² in discovery; p = 6.78 × 10⁻³ in validation), confirming dMMR as a class-level prognostic designation independent of which MMR gene is altered. Multivariable Cox regression demonstrated that POLE-ultramutated status retained an independent favorable effect (HR = 0.62, p = 0.038 in MSK; HR = 0.35, p = 0.028 in TCGA) after adjustment for age, histology, and sample type, while the favorable dMMR effect was largely accounted for by histologic context. Critically, a pathogenicity-aware sensitivity analysis revealed that the exceptional survival of the POLE subgroup is confined to canonical exonuclease-domain hotspot mutations (event rate 0.9% in MSK), whereas POLE variants of uncertain significance behave indistinguishably from NSMP-like tumors. Consistent with this finding, tumor mutational burden (TMB) was markedly elevated in canonical pathogenic POLE cases (median 138.7 mut/Mb in MSK; 247.4 in TCGA) but not in POLE-VUS-only cases (median 29.0 and 15.0, respectively; p < 0.001 between groups in both cohorts), confirming that the ultramutator phenotype is confined to canonical pathogenic POLE variants. We additionally characterize Uterine Clear Cell Carcinoma as a distinct histologic entity (n = 73; 3.0%) and report the POLE + TP53 co-mutant group (n = 90; 3.8%). Together, these findings refine the molecular classification of EC in clinically meaningful ways: they support class-level immunotherapy eligibility based on dMMR status regardless of the specific MMR gene altered, demonstrate that POLE-ultramutated classification requires variant-level pathogenicity assessment, and identify TP53-mutant/CNH patients as the population with the most urgent unmet therapeutic need. Full article

Background: Live-attenuated Listeria monocytogenes (Lm) vectors are a clinically validated cancer immunotherapy platform, but translation requires reproducible, clinically realistic workflows for dose preparation and infusion. For live bacterial products, in-use stability and device compatibility can drive dose variability through adsorption, settling, and device losses. Methods: We developed and GMP-manufactured an attenuated Lm vaccine expressing human GUCY2C (Lm-GUCY2C) and performed translational characterization, including construct verification and immunogenicity readouts, and defined the administration-focused in-use stability and device compatibility. Post-thaw stability was assessed in primary cryovials and during preparation and delivery from 250 mL saline infusion bags using standard clinical devices (syringes/needles, filter-free IV tubing) and OnGuard2 closed-system components. Samples were collected over 24 h at room temperature, and viable Lm-GUCY2C were quantified by CFU recovery. Results: Lm-GUCY2C remained stable in thawed cryovials for 24 h with no significant CFU loss. High-dose infusion bags (3 × 10⁹ CFU/bag) maintained CFU recovery through 6 h, whereas low-dose bags (3 × 10⁸ CFU/bag) exhibited significant losses beginning at 3 h, supporting a practical in-use window of up to 2 h for low-dose preparations. OnGuard2 intravenous (i.v.) connectors did not measurably affect CFU recovery, while OnGuard2 vial adapters reduced recovery. Conclusions: This work provides an end-to-end, translationally focused characterization of a GMP-manufactured Lm cancer vaccine, including clinically actionable in-use handling constraints and device compatibility. These data define preparation and administration guardrails (notably, time-to-infusion limits for low-dose bag preparations) that can improve dose accuracy and reproducibility in clinical testing. Full article

Background: Locally advanced rectal cancer (LARC) management has evolved, but surgery (total mesorectal excision, TME) remains the curative cornerstone. Total neoadjuvant therapy (TNT) and organ preservation (OP) have emerged as response-adaptive strategies. We conducted a state-of-the-art systematic review to critically appraise TNT efficacy, trade-offs, OP feasibility, and emerging biomarkers. Methods: Following PRISMA 2020 guidelines, we searched PubMed, MEDLINE, Scopus, and EMBASE (1990–March 2026) plus ASCO/ESMO abstracts (2020–2026). We included phase II/III randomised controlled trials and major prospective studies evaluating neoadjuvant strategies in non-metastatic LARC. Risk of bias was assessed using RoB 2. Given heterogeneity, a narrative synthesis was performed (PROSPERO: CRD420251252675). Results: From 2847 records, 45 publications (30 trials) were included. For high-risk LARC (cT4, cN2, EMVI+, MRF+, tumour deposits), TNT improves disease-free survival and reduces distant metastases versus standard chemoradiotherapy (RAPIDO, PRODIGE 23, STELLAR, TNTCRT). However, TNT increases locoregional recurrence risk with short-course radiotherapy (RAPIDO: 10% vs. 6%; Polish II: no sustained overall survival benefit). Organ preservation is achievable in expert centres (OPRA: 54% 5-year TME-free survival; OPERA; CAO/ARO/AIO-16), but surgery remains the durable standard for most patients. De-escalation (PROSPECT, CONVERT, FOWARC, OCUM) avoids radiotherapy in low-risk (mrMRF−) patients without compromising local control. Lateral pelvic lymph node involvement (LPLN+) remains a negative prognostic factor even after TNT. Immunotherapy added to TNT (UNION, STELLAR II, SPRING-01, PRECAM) increases pCR rates (40–60%) but remains investigational. ctDNA-guided adaptation (CINTS-R) is feasible but requires mature data. Conclusions: Surgery (TME) is the definitive curative treatment for LARC. TNT is a preferred intensification strategy for high-risk patients, but trade-offs between systemic and local control must be individualised. Organ preservation is safe only for selected patients in expert centres. Immunotherapy-TNT combinations and ctDNA guidance are promising but not yet standard. This review provides an evidence-based roadmap for integrating these advances without losing sight of surgery’s central role. Full article

Background: Childhood cancer survival now approaches 80% in high-income countries, yet most survivors face lifelong toxicity. This review examines the interplay between treatment efficacy, relapse prevention, and therapy-related complications. Methods: Narrative synthesis of landmark pediatric oncology trials (2000–2026), including AALL1731 (blinatumomab), ELIANA/PLAT-02 (CAR T-cell), and GD2-CART01 (neuroblastoma), with comparative analysis of efficacy and toxicity. Results: In AALL1731, adding blinatumomab to chemotherapy improved 3-year disease-free survival from 87.9% to 96.0% (HR = 0.39, 95% CI: 0.27–0.56, p < 0.001), but increased sepsis from 5.1% to 14.8%. Comparison between AALL1731 (front-line blinatumomab) and ELIANA (CAR T-cell in relapsed disease) reveals that earlier immunotherapy deployment yields better outcomes: 96% DFS vs. 48% 3-year EFS, respectively. In GD2-CART01, early use (after 1–2 prior lines) achieved 89% 5-year survival vs. 43% with delayed use (HR = 0.31). Approximately 95% of survivors experience ≥1 late effect, with 60–90% carrying chronic conditions into adulthood. Conclusions: Immunotherapy transforms outcomes, but timing is critical, as earlier deployment dramatically improves survival. Toxicity remains pervasive, requiring systematic mitigation strategies. Full article

Background: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and a leading cause of cancer-related mortality worldwide. Growing evidence indicates that metabolic syndrome components, including obesity, insulin resistance, and hyperglycemia, contribute to PCa development, and progression to more aggressive form. At the same time, standard treatments such as androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) significantly improve oncologic outcomes but are associated with adverse metabolic effects, including increased fat mass, insulin resistance, and sarcopenia, potentially worsening patients’ overall metabolic profile and quality of life. Tumor progression in PCa is strongly driven by androgen receptor (AR) signaling, which is closely linked to cellular metabolic reprogramming, highlighting metabolism as a potential therapeutic target. Aim: The aim of this study was to evaluate and synthesize current evidence on the role of the ketogenic diet (KD) in PCa, with particular emphasis on its interaction with hormonal therapies, underlying metabolic and endocrine mechanisms, and its potential application as an adjunctive strategy in integrated oncologic care. Results: The KD, characterized by high fat and very low carbohydrate intake, induces a metabolic state of ketosis that reduces circulating glucose, insulin, and insulin-like growth factor 1 (IGF-1), potentially counteracting metabolic alterations associated with PCa and its treatments. Preclinical studies consistently demonstrate that carbohydrate restriction and KD can slow tumor growth, modulate key oncogenic pathways such as PI3K/AKT/mTOR, reduce systemic insulin signaling, and enhance survival in prostate cancer models. Additionally, emerging evidence suggests possible synergistic effects when KD is combined with standard therapies, including ADT and immunotherapy. Clinical data, although limited, indicate that low-carbohydrate dietary interventions may improve metabolic parameters and could delay biochemical progression, as suggested by increased prostate-specific antigen (PSA) doubling time. However, results across studies remain heterogeneous, and robust evidence on long-term oncologic outcomes is lacking. Conclusions: Overall, the KD represents a promising but still experimental strategy in PCa management, requiring careful nutritional supervision to avoid adverse effects such as unintended weight loss or sarcopenia. Further well-designed randomized clinical trials are needed to clarify its safety, efficacy, and role in routine clinical practice. Full article

Background/Objectives: Gliomas are among the most aggressive primary brain tumors in adults, characterized by profound molecular heterogeneity and poor response to conventional therapies. Immunotherapy has transformed outcomes in several cancers, yet glioma remains largely refractory, due in part to an immunosuppressive tumor microenvironment. Post-transcriptional regulation of gene expression is increasingly recognized as a key mechanism controlling immune cell function in tumors. Regnase-1, an endoribonuclease regulating the stability of inflammation- and immunity-related mRNAs, is a central modulator of immune responses; however, its role in glioma progression and immune modulation remains poorly understood. This study aimed to evaluate Regnase-1 expression in glioma and investigate its association with tumor grade, prognosis, and immune microenvironment characteristics. Methods: Regnase-1 transcript levels were evaluated by RT-PCR in tumor samples from 40 Moroccan glioma patients and validated using transcriptomic data from The Cancer Genome Atlas (TCGA, n = 672) and the Chinese Glioma Genome Atlas (CGGA, n = 959). Bioinformatic analyses and statistical assessments were performed using established pipelines. Results: Regnase-1 expression was significantly elevated in glioblastoma, IDH-wildtype tumors, and higher tumor grades, correlating with poorer overall survival, and emerging as an independent prognostic factor in the CGGA cohort. High Regnase-1 expression was associated with enrichment of pathways related to angiogenesis, hypoxia, invasion, and immune evasion. Tumors with elevated Regnase-1 showed reduced infiltration of effector immune cells (CD8⁺ T cells, Th1 cells) and increased presence of immunosuppressive populations, including regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages. Single-cell analyses further highlighted exhausted CD8⁺ T cells and regulatory T cells as major populations linked to Regnase-1 expression. Notably, Regnase-1 expression also exhibited strong positive correlations with multiple inhibitory immune checkpoint pathways. Conclusions: Elevated Regnase-1 expression defines an aggressive, immunosuppressive glioma phenotype and is associated with poor prognosis, supporting its potential as a prognostic biomarker and a target for immunomodulatory strategies. 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

Triple-negative breast cancer is an aggressive and heterogeneous type of invasive breast cancer (BC) in which the cancer cells lack estrogen and progesterone receptors, as well as expression of the human epidermal growth factor 2 protein. This cancer tends to grow and spread faster than other BC subtypes, and is associated with a poor prognosis due to early visceral and neurological recurrences. Multidisciplinary management includes surgery, chemotherapy, radiation therapy, and immunotherapy with targeted immune checkpoint inhibitors (ICIs). The introduction of ICIs has improved outcomes in patients with TNBC, particularly in the metastatic and neoadjuvant settings. Despite these advances, a significant proportion of patients either do not respond to treatment or develop resistance to it. TNBC mortality remains high, underscoring the urgent need to identify novel prognostic and predictive biomarkers to overcome resistance to immunotherapy. Following a brief overview of the clinical features and established biomarkers of TNBC, the current review focuses on immune checkpoint proteins (ICPs) beyond PD-1 and PD-L1, and on the potential use of soluble ICPs rather than the well-established membrane-bound assays. These soluble ICPs are produced through the alternative splicing of messenger (m)RNA or the cleavage/shedding of membrane-bound proteins. This is followed by an overview of current treatment and novel predictive targets in TNBC. Additionally, the involvement of the B- and T-lymphocyte attenuator (BTLA)/herpes virus entry mediator (HVEM)/CD160 pathway and its role in the pathogenesis of BC and TNBC are reviewed, highlighting the potential use of BTLA and HVEM as biomarkers. Full article