Search Results (1,303)

Barrett’s esophagus (BE), the intestinal metaplasia arising from chronic gastroesophageal reflux disease, is the principal identifiable precursor of esophageal adenocarcinoma (EAC), whose incidence rose from 0.4 to 2.8/100,000 person-years between 1975 and 2017 and whose prognosis, once symptomatic, remains poor. Because outcomes depend on intercepting the metaplasia–dysplasia–carcinoma sequence, diagnostic accuracy is decisive. White-light endoscopy with Seattle-protocol biopsy remains the reference standard, yet it is constrained by the following three interrelated weaknesses: sampling error, as random forceps biopsies interrogate only about 3.5% of the Barrett’s mucosa; poor reproducibility of dysplasia grading, with interobserver agreement of only κ 0.24–0.27 for the pivotal distinction of low-grade dysplasia; and a substantial burden of missed disease, with roughly one-quarter of EACs diagnosed within a year of an index endoscopy reported as nondysplastic. This review synthesizes the technologies converging to address these gaps. Advanced imaging, encompassing high-definition endoscopy, narrow-band imaging, acetic acid chromoendoscopy, and the optical-biopsy platforms confocal laser and volumetric laser endomicroscopy, raises dysplasia yield by approximately 34% over standard white-light examination. Image-enhanced endoscopy improves targeted detection while remaining complementary to structured biopsy sampling. Molecular, genetic, and epigenetic biomarkers, notably DNA-content abnormalities, p53 immunohistochemistry, and multi-gene methylation panels, add an objective read on progression risk. Their pairing with non-endoscopic sampling, including Cytosponge-TFF3, capsule endoscopy, exhaled volatile organic compounds, and circulating microRNA liquid biopsy, is reshaping screening at population scale, while artificial intelligence standardizes interpretation and narrows the expert–nonexpert gap. Together these advances point toward a risk-stratified, multimodal paradigm, though prospective validation and cost-effectiveness evidence remain prerequisites for guideline adoption. Full article

Background: Anastomotic leak (AL) is a major complication after esophagectomy, and gastric conduit perfusion is considered a key determinant of anastomotic integrity. Indocyanine green (ICG) fluorescence angiography is increasingly used for intraoperative perfusion assessment, although its clinical effect remains uncertain. We evaluated whether routine implementation of ICG assessment was associated with a lower incidence of AL compared with a historical no-ICG cohort, and explored intraoperative factors potentially associated with AL. Methods: Single-center before–after cohort study of consecutive adults undergoing Ivor-Lewis esophagectomy for cancer between January 2023 and December 2025, using a prospectively maintained database. ICG entered routine practice in March 2025, defining a historical no-ICG cohort and an ICG cohort. ICG (2 mL of a 25 mg/10 mL solution) was administered at three intraoperative timepoints; time to fluorescence (TTF), arcade–conduit fluorescence pattern, arterial blood gas values, and hemodynamic parameters were recorded. AL was defined according to Esophagectomy Complications Consensus Group criteria. Results: Sixty patients were included (ICG, n = 17; no-ICG, n = 43). AL occurred in 4/17 (23.5%) versus 5/43 (11.6%) patients (odds ratio 2.34, 95% CI 0.54–10.05; p = 0.256). Overall postoperative morbidity, conduit necrosis, pulmonary and infectious complications, reintubation, and 90-day mortality did not differ; a single death occurred, in the no-ICG cohort. All TTF values were below 60 s (range 23–46 s) and did not differ between patients with and without AL, nor did the fluorescence pattern; ICG never modified the planned anastomotic site or prompted additional conduit resection. Exploratory within-ICG analyses showed lower thoracic-phase PaO₂ and PaCO₂ and higher pH in patients who developed AL. Conclusions: Routine qualitative ICG assessment of gastric conduit perfusion was feasible; however, this small before–after cohort was insufficient to determine its effect on AL. Larger studies using standardized quantitative fluorescence assessment are required. Full article

Background and Objectives: Intra-corporeal esophagojejunostomy after totally laparoscopic total gastrectomy (TLTG) remains one of the most technically demanding steps of minimally invasive gastric surgery. The management of the common entry hole in linear stapler-based reconstructions still relies on advanced intra-corporeal suturing. The sutureless L-shape esophagojejunostomy with endoscopic assistance (SLEJ) technique, previously described by our group, was developed to overcome this limitation by combining an L-shaped linear stapler configuration with intraoperative endoscopic quality control. Building upon our initial results on the perioperative feasibility of the technique, the present study aimed to evaluate its intermediate-term anastomotic, functional, and oncological outcomes. Materials and Methods: Patients who underwent TLTG with D2 lymph node dissection and SLEJ reconstruction for gastric cancer between July 2024 and January 2026 were evaluated. Eligibility criteria included a minimum postoperative follow-up of six months, clinical and endoscopic surveillance, and complete contrast-enhanced thoraco-abdominopelvic computed tomography records. Protocol-based upper gastrointestinal endoscopy was performed at six-month intervals irrespective of symptoms to objectively assess anastomotic lumen width, mucosal healing, reflux findings, and possible intraluminal recurrence. The primary endpoint was anastomosis complication-free survival (anastomotic stenosis, alkaline reflux/reflux esophagitis, marginal ulcer, bleeding due to ulceration, and intraluminal recurrence); secondary endpoints were disease-free survival (DFS), local recurrence and changes to nutritional status. Results: A total of 26 patients (18 men and 8 women; mean age 59.0 ± 7.8 years) were analyzed. Anastomotic stricture developed in two patients and was successfully managed with two sessions of endoscopic balloon dilation in both. Similarly, alkaline reflux was documented in two additional patients and resolved under medical treatment. None of the patients required surgical revision. The mean ACFS follow-up duration was 12.42 months with ACFS rates of 92.3% at six months and 81.1% from the twelfth month onward. No local anastomotic recurrence was detected during follow-up. Disease progression occurred in four patients (15.4%), presenting as distant organ metastasis (n = 2) or peritoneal carcinomatosis (n = 2). The mean DFS follow-up duration was 12.62 ± 6.18 months, and the twelve-month OS and DFS rates were 82.1% and 84.0%. Postoperative body weight decreased significantly compared with preoperative values (76.69 ± 15.59 kg vs. 63.23 ± 10.55 kg; p < 0.001). A significant decrease was observed in the mean SMI between the preoperative and follow-up assessments (p < 0.001). The mean preoperative SMI was 49.90 ± 9.04 cm²/m², compared with 44.53 ± 7.98 cm²/m² at follow-up. No statistically significant changes were observed between the preoperative and follow-up periods for serum albumin and PNI variables (p = 0.703 and p = 0.970). Conclusions: The present intermediate-term analysis suggests that the SLEJ technique is feasible and associated with acceptable intermediate-term anastomotic, functional, and oncological outcomes in this preliminary single-center cohort. By standardizing common entry-hole management without intra-corporeal suturing and incorporating intraoperative endoscopic quality control, the technique offers a feasible alternative to established linear stapler-based reconstructions. Full article

Background: Circulating tumor DNA (ctDNA) has emerged as a clinically valuable biomarker for cancer detection, treatment monitoring, and minimal residual disease assessment. Despite its growing clinical utility, the biological mechanisms governing ctDNA release remain incompletely understood. The objective of this study was to investigate how chemotherapy-induced cytotoxicity and chemoresistance influence the kinetics and fragmentation patterns of cfDNA released by cancer cells in vitro. Methods: Human lung adenocarcinoma (A549) and esophageal adenocarcinoma (FLO-1, OE19) cell lines were used to investigate cell-free DNA (cfDNA) release and fragmentation in vitro. Cancer cells were treated with chemotherapy (cisplatin and 5-fluorouracil), and cfDNA released into the culture medium was quantified as total cfDNA by Qubit fluorometry and mutation-specific cfDNA by droplet digital PCR (ddPCR). A cisplatin-resistant OE19 model was generated to directly compare cfDNA release kinetics between chemosensitive and chemoresistant cells. Fragment size distributions were determined and evaluated alongside cell death mechanisms assessed by flow cytometry. Results: cfDNA release correlated positively with viable tumor cell number across all cell lines. Chemotherapy increased per-cell cfDNA release in all cell lines. Chemosensitive OE19 cells exhibited significantly higher cfDNA release compared to chemoresistant OE19 cells following cisplatin exposure, with distinct temporal release kinetics. Additionally, chemotherapy treatment induced a shift toward the release of larger DNA fragments in both chemosensitive and resistant cells. This was accompanied by changes in PI-positive and Annexin V/PI double-positive cell populations, suggesting altered cell death processes following cisplatin treatment. Conclusions: Chemotherapy-induced cytotoxicity significantly influences cfDNA release kinetics and fragmentation patterns, with distinct effects in chemosensitive and chemoresistant cancer cells. These findings provide mechanistic insight into tumor-derived DNA release biology and may have important implications for the interpretation, timing, and standardization of liquid biopsy testing during treatment. Furthermore, they establish in vitro cancer models as a valuable platform for studying cfDNA dynamics and informing preclinical therapeutic development. Full article

Objective: This study evaluates the prognostic significance of pretreatment [¹⁸F]FDG PET/CT metabolic parameters in esophageal cancer and identifies independent predictors of overall survival (OS). Methods: This retrospective single-center study included 152 treatment-naïve patients with histopathologically confirmed esophageal cancer who underwent staging [¹⁸F]FDG PET/CT between May 2015 and August 2025. SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured for the primary tumor. Overall survival was analyzed with Kaplan–Meier and Cox proportional hazards models, and cut-off values were derived by receiver operating characteristic (ROC) analysis. Results: During a median follow-up of 70 months, 106 patients (69.7%) died. In comparisons of median values, MTV and TLG were higher in patients who died (p = 0.004 and p = 0.035), whereas SUVmax and SUVmean did not differ; both volumetric indices were associated with shorter OS as continuous variables and when dichotomized at their ROC-derived cut-offs. Their discrimination was comparable and modest (AUC 0.647 and 0.608). A multivariable model incorporating high TLG achieved a Harrell’s C of 0.715, at least as high as the primary MTV-based model (C = 0.687), so the data do not establish MTV as superior to TLG. In the primary multivariable model, distant metastasis (HR 2.46, 95% CI 1.53–3.98, p < 0.001), and high MTV (≥11.44 cm³; HR 1.79, 95% CI 1.18–2.71, p = 0.006) remained independent predictors of death. Conclusions: Volumetric [¹⁸F]FDG PET/CT indices (MTV and TLG) rather than SUVmax carried independent prognostic information for overall survival, alongside distant metastasis, supporting their use as an adjunct to established staging in pretreatment risk stratification, pending prospective multicenter validation. Full article

Immune checkpoint blockade has changed the management of several digestive system cancers, but its impact is highly context dependent. This review evaluates evidence for esophageal, gastric and gastroesophageal junction, colorectal, hepatocellular, biliary tract and gallbladder, and pancreatic cancers. Randomized phase III trials have established chemoimmunotherapy or dual-checkpoint strategies in advanced esophageal cancer, biomarker- and regimen-dependent first-line therapy in gastric cancer, PD-1-based therapy for MSI-H/dMMR colorectal cancer, atezolizumab–bevacizumab and STRIDE for unresectable hepatocellular carcinoma, and chemoimmunotherapy for advanced biliary tract cancer. Recent results also expand perioperative treatment: neoadjuvant checkpoint blockade produces high pathological response rates in dMMR colon cancer, adjuvant atezolizumab plus mFOLFOX6 improves disease-free survival in stage III dMMR colon cancer, and perioperative serplulimab improves event-free survival in PD-L1-positive resectable gastric cancer. These advances coexist with important negative findings. Pembrolizumab-containing therapy did not meet superiority end points in KEYNOTE-062, the initial adjuvant signal in IMbrave050 was not sustained, and unselected pancreatic ductal adenocarcinoma remains largely resistant to checkpoint blockade. Early vaccine, cellular, TIGIT, radiomics, spatial, and multi-omics studies remain hypothesis-generating and require external or randomized validation. Clinical interpretation should integrate evidence maturity, biomarker validity, immune-related toxicity, patient-reported outcomes, cost, access, and manufacturing demands rather than response rate alone. Full article

Temporal molecular events during early esophageal squamous carcinogenesis remain incompletely defined, in part because human precursor tissues are difficult to obtain sequentially. We used the N-nitrosomethylbenzylamine (NMBA)-induced rat model to characterize stage-associated transcriptional programs during esophageal squamous carcinogenesis. Vehicle-control reference esophageal tissues and NMBA-treated esophageal tissues, collected at weeks 6 and 29, were profiled using Affymetrix Rat Genome 230 2.0 arrays, followed by pathway analysis and qRT-PCR validation of selected genes. Relative to vehicle-control reference tissues, 173 genes were differentially expressed at week 6, whereas 1628 genes were differentially expressed at week 29, indicating marked expansion of transcriptional dysregulation during carcinogenic progression. Sixteen genes were differentially expressed only at week 6, while 157 genes were altered at both time points. Pathway analysis suggested that inflammatory and immunologic processes were prominent during the early response to NMBA exposure, whereas late-stage carcinogenesis was characterized by NRF2-associated oxidative-stress response and dysregulation of multiple glutathione S-transferase family members. A subset of progression-associated genes, including Defb4, Gsta2, Sbsn, Spink5, Plcd4, Hbb, and Hba-a2, showed increasing dysregulation from week 6 to week 29. These findings define temporally distinct molecular programs in NMBA-induced esophageal squamous carcinogenesis and provide a framework for prioritizing candidate pathways and genes relevant to esophageal cancer prevention, early detection, and progression biology. Full article

Background: Esophageal squamous cell carcinoma (ESCC) remains highly aggressive and continues to limit clinical treatment for substantial cancer-associated morbidity and mortality worldwide. Despite advances in therapeutic interventions the lack of effective molecularly targeted treatments continues to restrict clinical management beyond conventional chemotherapy and radiotherapy. Among these therapeutic targets the ribosomal S6 kinase 4 (RSK4) has gained considerable attention because of its critical involvement in ESCC progression, survival and proliferation, suggesting its potential as a potential target for anticancer drug development. Methods: A series of thiazole-clubbed pyrimidine linked hydrazone hybrids (1–14) were synthesized via 4-aminothiazole-5-carbohydrazide functionalized intermediates and fully characterized and evaluated for their inhibitory activity against RSK4. Results: Biological assessment demonstrated that the synthesized analogues exhibited remarkable potency, with IC₅₀ values between 15.32 ± 1.35 and 54.61 ± 2.17 nM compared with the reference inhibitor BI-D1870 (IC₅₀ = 33.16 ± 1.34 nM). Among the evaluated compounds, 2, 8, 9, 13 and 14 emerged as the most potent candidates and showed pronounced activity towards RSK4. For further insights into the molecular basis of their activity the lead candidates were subjected to computational investigations, such as molecular docking, molecular dynamics simulations, in silico ADMET and ProTox-3.0 characterization. The computational analyses provided structural and pharmacological insights into experimentally observed RSK4 inhibitory activity, like predicted interactions, stability dynamically and preliminary ADMET/toxicity characteristics. This study supports the need for further optimization and experimental validation of the identified RSK4 active lead candidates. Conclusions: These findings highlight the thiazole-clubbed pyrimidine-linked hydrazone scaffold as a potential chemotype for promising scaffolds targeting RSK4 lead discovery, and the identified candidates warrant further investigation into ESCC cellular models to establish anticancer efficacy and pathway-level activity. Full article

Background: Human papillomavirus (HPV) is the most common sexually transmitted infection and the primary etiological agent of cervical cancer. Despite the high global disease burden, the Middle East and North Africa (MENA) region faces substantial challenges in HPV prevention and control. This narrative review aimed to synthesize existing evidence on the prevalence, genotypic distribution, awareness, vaccination status, clinical outcomes, and the role of HPV in non-cervical malignancies in the MENA region. Methods: PubMed, Web of Science, Scopus, and Google Scholar were searched, and 122 studies were included. Findings were synthesized qualitatively and descriptively. Cohort studies, systematic reviews, and meta-analyses were prioritized to support inferences about associations and potential causal relationships. Results: HPV prevalence in the general female population of the MENA region ranged from 4.7% to 53.3%, exceeding 90% in high-risk groups and patients with malignancies. The most common genotypes were HPV16 and HPV18; however, distribution patterns varied across populations. Key risk factors included younger age, multiple sexual partners, early age at first sexual intercourse, smoking, and alcohol consumption. General awareness was low to moderate, and vaccination coverage was very low in most countries. Barriers included lack of knowledge, fear of side effects, religious concerns, and social stigma. Evidence also indicates an association between HPV and non-cervical malignancies (head and neck, esophageal, gastric, breast, and thyroid cancers), with HPV DNA detected in tumor tissues. Conclusions: HPV poses a significant public health challenge in the MENA region, characterized by high prevalence, genotypic diversity, limited knowledge and awareness, and unsatisfactory vaccination coverage. Expanding screening and vaccination through financial support, culturally and religiously appropriate education, and longitudinal studies to monitor genotypic changes and associations with other malignancies are essential measures to reduce the burden of HPV-related diseases in the region. Full article

Gastrointestinal (GI) cancers represent a diverse group of malignancies that remain a major cause of cancer-related morbidity and mortality worldwide. Their management is increasingly complex, reflecting differences in tumor biology, anatomical location, stage, and molecular profile. In recent years, advances in molecular diagnostics, immunotherapy, and targeted treatment have moved clinical decision-making beyond a purely organ- and stage-based approach toward more individualized, biomarker-guided care. This narrative review summarizes established and emerging biological and targeted therapies used in esophageal, gastric and gastroesophageal junction, colorectal, pancreatic, hepatocellular, and biliary tract cancers. It focuses on immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4; HER2-directed monoclonal antibodies and antibody–drug conjugates; antiangiogenic and anti-EGFR therapies; and newer strategies involving CLDN18.2, FGFR2b, and tumor-agnostic alterations such as NTRK fusions. The review also considers the predictive biomarkers used to guide treatment selection and the growing integration of systemic therapy with surgery in neoadjuvant, perioperative, adjuvant, and conversion settings. However, clinical efficacy alone does not determine whether new treatments become part of routine practice. Regulatory approval, reimbursement, access to molecular testing, and the availability of specialized multidisciplinary care are equally important. The rapidly evolving treatment landscape for GI cancers therefore requires clinical decisions that account for tumor biology, anatomical resectability, molecular eligibility, expected benefit, treatment-related toxicity, and local access to therapy. Expanding access to comprehensive biomarker testing and effective molecularly guided treatments will be essential to translate progress in precision oncology into more personalized and equitable care for patients with GI cancers. Full article

Immune checkpoint inhibitors have improved outcomes in esophageal cancer across settings, yet clinical benefit remains heterogeneous, with current host-derived biomarkers incompletely predicting response. This mini review evaluates recent studies that integrate gut or intratumoral microbial features with host immune, molecular, or metabolic assessment in esophageal cancer. We classify the evidence using a four-level hierarchy of host-microbiome integration: ecological association, functional association, mechanistic integration, and clinical predictive integration. Tissue studies reveal compartment-specific relationships between microbial diversity or individual taxa and immune architecture, whereas treatment cohorts identify bacterial and fungal signatures associated with pathological or immunotherapy response. Mechanistic studies offer the strongest biological evidence, most notably the Lactobacillus salivarius-indole-3-lactic acid-AhR/NF-κB axis, which drives CD8-positive T-cell exhaustion and resistance to anti-PD-1 therapy. However, biological integration is substantially more advanced than clinical response prediction. Small cohorts, heterogeneous regimens, contamination of low-biomass samples, coarse taxonomic (rather than functional) resolution, confounding by histology, multi-omic layers measured in different patients, and lack of external validation currently jeopardize integration of microbiome to guide treatment. Future studies should use longitudinal, multicenter, compartment-matched sampling and test whether microbial genes or metabolites improve patient selection and predict clinical response beyond established clinical and host biomarkers. Full article

Esophageal cancer is a common malignancy of the upper gastrointestinal tract that is associated with high incidence and mortality rates. Radiotherapy constitutes a cornerstone therapeutic modality for esophageal cancer. In radiotherapy, ionizing radiation is used to eliminate tumor cells through direct DNA damage and indirect reactive oxygen species (ROS)-mediated effects. However, clinical outcomes are frequently limited by interpatient heterogeneity and intrinsic tumor radioresistance. This review systematically describes the determinants of radiosensitivity in esophageal cancer within the established radiobiological framework of the “6Rs”: DNA damage repair (Repair), which is mediated by γ-H2AX phosphorylation, PARP family enzymes, and nonhomologous end joining (NHEJ) and homologous recombination (HR) pathways; cell cycle redistribution (Redistribution), which is regulated by G1/S and G2/M checkpoint dynamics; tumor repopulation (Repopulation), which is driven by cancer stem cell activity during fractionated treatment; reoxygenation (Reoxygenation), which is modulated through HIF-1α signaling and ROS homeostasis; intrinsic radiosensitivity (Radiosensitivity), which reflects interindividual and histopathological variability; and reactivation of antitumor immune responses (Reactivation), which enhances efficacy by remodeling the tumor immune microenvironment. Furthermore, regulated cell death mechanisms, including ferroptosis, autophagy, and apoptosis, significantly modulate radiotherapeutic responses. Elucidating these interconnected mechanisms provides a robust theoretical foundation for developing targeted interventions, identifying predictive biomarkers, and advancing precision radiotherapy strategies to optimize clinical outcomes for patients with esophageal cancer. Full article

Chronic kidney disease (CKD) may reduce physiologic reserve among patients with esophageal cancer, but evidence beyond postoperative cohorts is limited. Using the TriNetX Global Collaborative Network, we studied adults with esophageal cancer diagnosed during 2010–2023. CKD stages 3–5 were defined by diagnostic codes plus estimated glomerular filtration rate < 60 mL/min/1.73 m² within 6 months before or on the index date; dialysis-dependent patients were excluded. Non-CKD patients served as comparators. Prespecified outcomes from day 1 to up to 3 years included all-cause mortality, subsequent recorded metastatic diagnosis, pneumonia, sepsis, blood transfusion, and major adverse cardiovascular events. Propensity score matching produced 832 pairs. All-cause mortality was not significantly higher in the overall cohort with CKD stages 3–5 than in the non-CKD cohort (HR, 1.13; 95% CI, 0.98–1.31; p = 0.099), whereas CKD stages 4–5 were associated with higher mortality in the stage-specific analysis (HR, 1.46; 95% CI, 1.03–2.06; p = 0.031). CKD stages 3–5 were also associated with higher risks of blood transfusion (HR, 1.45; 95% CI, 1.04–2.01; p = 0.025) and MACEs (HR, 1.22; 95% CI, 1.02–1.47; p = 0.027), and with a lower risk of subsequent recorded metastatic diagnosis (HR, 0.80; 95% CI, 0.65–0.99; p = 0.036). These findings suggest that the associations of CKD with post-diagnostic outcomes varied by outcome type, with higher mortality observed in the separate CKD stages 4–5 analysis. Full article

Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker for detecting minimal residual disease (MRD) and predicting recurrence after curative treatment, yet evidence in esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric cancer has largely been examined within individual tumor types. In this scoping review, we mapped this evidence across all three malignancies and clarified key methodological and clinical considerations. Following the PRISMA-ScR guidelines, we searched PubMed, Scopus, and the Cochrane Library (3 April 2026) for studies linking ctDNA to disease-free, recurrence-free, or overall survival after curative-intent treatment. Twenty-seven studies (1746 patients; 10 ESCC, 4 EAC, 8 gastric, and 5 mixed) were included. Across every tumor type, postoperative ctDNA MRD was the most informative timepoint, with independent multivariable hazard ratios for disease-free, recurrence-free, or event-free survival of 2.8 to 21.8, whereas preoperative ctDNA was seldom prognostic. Serial monitoring further improved performance and flagged recurrence 78 to 278 days before imaging. Tumor-informed assays showed higher sensitivity than tumor-agnostic ones (80% vs. 35%), though direct comparisons were limited; correction for clonal hematopoiesis was essential for tumor-agnostic assays, and blood-based assays performed poorly in diffuse-type and peritoneal disease. Postoperative ctDNA MRD is a consistent, independent prognostic biomarker across upper gastrointestinal cancers that adds prognostic information beyond conventional staging and pathological response, supporting prospective interventional trials of ctDNA-guided management. Full article

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) emerged as one of the most promising next-generation immune checkpoint targets following the success of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. TIGIT suppresses antitumor immunity through interaction with cluster of differentiation 155 (CD155), inhibition of CD226-mediated co-stimulation, and promotion of immunosuppressive regulatory T-cell (Treg) activity within the tumor microenvironment (TME). Strong preclinical evidence demonstrated that TIGIT blockade, particularly in combination with PD-1/PD-L1 inhibition, restored T-cell and natural killer (NK) cell function and produced durable antitumor responses in multiple tumor models, leading to rapid clinical development. Despite this compelling biological rationale, most late-stage clinical programs failed to reproduce early success. Although the phase II CITYSCAPE trial showed encouraging activity in PD-L1-high non-small cell lung cancer (NSCLC), subsequent phase III trials, including SKYSCRAPER-01, SKYSCRAPER-02, SKYSCRAPER-03, SKYSCRAPER-14, AdvanTIG-302, KEYVIBE, and STAR-221, failed to improve survival outcomes or meet primary endpoints. The notable exception was SKYSCRAPER-08 in esophageal squamous cell carcinoma, suggesting that TIGIT blockade may be effective only in selected biological contexts. This review critically examines the molecular biology of the TIGIT–CD155–CD226 axis, its role in immune regulation and tumor immune evasion, and the preclinical and clinical evidence supporting TIGIT-targeted therapy. Particular emphasis is placed on understanding the causes of clinical failure, including CD226 loss during T-cell exhaustion, checkpoint network redundancy, Fc-engineering uncertainty, immunosuppressive TMEs, inadequate biomarker-guided patient selection, and tumor-type-specific dependence on the TIGIT pathway. We also present original bioinformatics analyses demonstrating that broader checkpoint network signatures outperform TIGIT expression alone for patient stratification. Finally, we evaluate emerging solutions including biomarker-guided precision immunotherapy, Fc-optimized antibodies, bispecific checkpoint inhibitors, TIGIT-engineered chimeric antigen receptor T-cell (CAR-T) cells, radiotherapy combinations, and multi-checkpoint blockade. Collectively, current evidence suggests that the future of TIGIT-directed therapy lies not in universal checkpoint inhibition but in biologically informed, precision-guided immunotherapy strategies. Full article