Search Results (18,775)

Androgen dysregulation impairs the homeostasis of the prostate, hair follicles, and ovaries, driving the pathogenesis of prostate cancer (PCa), benign prostatic hyperplasia (BPH), androgenetic alopecia (AGA), and polycystic ovary syndrome (PCOS). Current antiandrogen therapies are constrained by drug resistance, off-target toxicity, and limited long-term efficacy. Plant extracts, enriched with bioactive constituents such as polyphenols, alkaloids, and flavonoids, represent promising multi-target candidates. Therefore, focusing on plant extracts—particularly those of dietary origin—this review summarized the mechanisms by which they regulate androgen-dependent and androgen-independent signaling pathways, and recent advances in nutritional interventions targeting androgen-responsive organs. Furthermore, it discussed the multi-component combined effects and factors affecting in vivo exposure of plant extracts, including metabolic transformation and tissue distribution, which may influence the anti-androgenic activity. In summary, anti-androgenic plant extracts primarily target androgen synthesis and AR signaling across various androgen disorder models, with crosstalk into cell growth and cycle, anti-inflammatory pathways, and regulation of growth factors. This multi-target regulation relies on the mixture effects of plant extracts. Future research should focus on three directions: extract standardization, clinical validation, and advanced delivery systems. Full article

Background/Objectives: The advent of immune checkpoint inhibitors (ICIs) and targeted therapies has revolutionized advanced melanoma treatment but introduced unique immune-related adverse events (irAEs). Hematological irAEs (Hem-irAEs) are rare but carry disproportionately high morbidity and mortality. This review systematically synthesizes current literature to comprehensively understand the incidence, pathophysiology, clinical presentation, and management of Hem-irAEs in modern melanoma therapy. Methods: A comprehensive Web of Science literature search (January 2015 to January 2026) identified studies reporting hematological adverse events associated with melanoma immunotherapy and targeted therapies. After screening 2274 records, 130 relevant studies were included for quantitative data extraction, focusing on incidence rates and toxicity grading. Results: Hem-irAEs occur infrequently (under 4% overall incidence for ICIs) but possess staggering mortality rates between 12% and 15.5%. The most common manifestations are immune thrombocytopenia (ITP), autoimmune hemolytic anemia, and neutropenia. Combination regimens significantly amplify toxicity frequency and severity. Diagnosis requires meticulous baseline monitoring and bone marrow biopsies to differentiate peripheral destruction from central marrow failure. First-line management mandates ICI discontinuation and high-dose corticosteroids, utilizing targeted second-line immunosuppressants for refractory syndromes. Conclusions: Hem-irAEs embody a profound clinical paradox: while mild toxicities often herald a robust anti-tumor response, severe hematological events drastically increase non-cancer mortality, negating these oncological benefits. Navigating this “double-edged sword” demands a paradigm shift toward proactive risk stratification. Integrating predictive biomarkers including baseline autoantibodies, Human Leukocyte Antigens (HLA) profiling, and systemic inflammatory indices is crucial to identify vulnerable populations before treatment. Optimizing outcomes requires highly personalized vigilance to balance the life-saving efficacy of immunotherapy against the catastrophic threat of hematopoietic failure. Full article

Advances in healthcare have led to substantial growth in the global population of cancer survivors, yet young adult cancer survivors (YACS) aged 18–39 years remain an underrepresented population in cancer survivorship research. This review examines the health challenges and psychosocial factors that shape nutritional status in YACS, with the aim of informing age-appropriate nutritional care. YACS face significant financial and psychosocial demands unique to this life stage, balancing education, early careers and family responsibilities. They report greater unmet nutritional and health needs than other age cohorts, in addition to concerns regarding long-term side effects, financial strain, fear of cancer recurrence and increased responsibility for managing their own care. Cancer treatment can cause nutrition impact symptoms (e.g., nausea, taste changes, fatigue, dysphagia and gastrointestinal (GI) disturbances) that may persist for years, and YACS are vulnerable to late effects such as endocrine dysfunction, cardiometabolic disease, chronic pain and osteoporosis, all of which can be influenced by diet. Poor dietary patterns have been observed in YACS, indicating low intakes of fruits, vegetables, fibre and dairy, and higher consumption of saturated fat, sodium and processed foods. This narrative review evaluated fourteen nutritional intervention studies targeting YACS aged 18–39. Most existing interventions demonstrate minimal recruitment and retention rates, small sample sizes, and a reliance on self-report methods rather than objective nutritional measures. These limitations highlight the need for a deeper understanding of YACS’ specific nutritional needs and more effective strategies to engage this cohort. Future research should prioritise larger, more representative samples, incorporate objective nutritional and clinical measures, and explicitly address psychosocial and age-related barriers to healthy eating in young adulthood. Full article

Background/Objectives: Epithelial ovarian cancer (EOC) remains a gynecologic malignancy with a poor prognosis, with a 5-year survival of approximately 29% in advanced-stage disease. Despite cytoreductive surgery and platinum- and taxane-based chemotherapy, most patients relapse within 2 years. Major therapeutic barriers include chemoresistance, molecular heterogeneity, and an immunosuppressive peritoneal microenvironment. This review summarizes emerging therapeutic strategies for EOC, their mechanisms of action, and their potential to overcome treatment resistance. Methods: PubMed/MEDLINE was searched for preclinical studies, phase I–III clinical trials, systematic reviews, and meta-analyses addressing novel ovarian cancer therapies and resistance mechanisms. Results: The review covers molecularly targeted therapies, immunotherapies, metabolic and epigenetic approaches, cellular and gene therapies, targeted drug-delivery systems, and locoregional and physical modalities. Strategies include PARP inhibitors, antiangiogenic agents, antibody–drug conjugates, pathway inhibitors, immune checkpoint inhibitors, cancer vaccines, adoptive cell therapies, metabolic and epigenetic modulators, CAR-T, CAR-NK, CRISPR/Cas9, HIPEC, PIPAC, ablation, photodynamic therapy, and sonodynamic therapy. Conclusions: The clinical maturity of these approaches varies substantially. PARP inhibitors, antiangiogenic agents, selected antibody–drug conjugates, MAPK-directed therapy in LGSOC, and HIPEC in selected settings have the strongest clinical support. Most immune combinations, metabolic and epigenetic therapies, adoptive cell therapies, gene-editing approaches, and novel delivery or physical modalities remain early clinical or predominantly preclinical. Progress will depend on biomarker-guided patient selection, reassessment of evolving resistance mechanisms, and rational treatment sequencing and combinations. Full article

Background/Objectives: The advent of immune checkpoint inhibitors (ICIs) and targeted therapies has revolutionized advanced cutaneous melanoma care, shifting it from an acutely fatal illness to a chronic, manageable condition. While extending survival, these modern therapies introduce a new spectrum of persistent immune-related adverse events (irAEs) and long-term toxicities. This study aims to explore the “Toxicity-HRQoL Paradox” to comprehensively evaluate the true price of survival across the melanoma treatment continuum. Methods: This narrative review, based on a systematic database search, synthesizes quantitative patient-reported outcomes, health-related quality of life (HRQoL) trajectories, and health-economic data. It evaluates the impact of surgical, regional, and modern systemic therapies utilizing data derived from validated instruments, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), EuroQol 5 Dimensions (EQ-5D), Functional Assessment of Cancer Therapy-Melanoma (FACT-M), and comprehensive score for financial toxicity (COST). Results: Historically, extensive locoregional surgeries and high-dose interferons caused profound, debilitating drops in physical and overall QoL. Today, modern systemic therapies are associated with high rates of severe (Grade ≥ 3) acute toxicities and irreversible chronic conditions, such as permanent endocrinopathies. Despite this, global HRQoL frequently remains stable or even improves. This “toxicity-HRQoL paradox” occurs because the profound psychological relief of durable disease control effectively offsets the physical symptom burden. Furthermore, neoadjuvant ICI approaches demonstrate superior long-term HRQoL by enabling tailored surgical de-escalation. Ultimately, extended survivorship unmasks hidden burdens, revealing high prevalences of fear of cancer recurrence (FCR) (81–86%) and substantial financial toxicity. Conclusions: Despite the severe physical toxicities of modern melanoma treatments, the psychological benefit of survival largely preserves overall HRQoL. However, optimizing the modern survivorship experience requires the widespread adoption of melanoma-specific HRQoL tools and proactive, multidisciplinary care models to manage chronic toxicities, psychosocial distress, and financial burdens. Full article

Background/Objectives: In Lebanon, the economic crisis since 2019 has severely strained healthcare infrastructure, yet its impact on cancer treatment adherence remains incompletely characterized. This study assessed factors associated with treatment delay and regimen modification to identify barriers to optimal cancer care among Lebanese patients. Methods: This multicenter, cross-sectional study was conducted in five tertiary hospitals in Beirut, Lebanon, between 13 June 2024, and 27 June 2025. Demographic, clinical and treatment data were collected via a structured questionnaire. Bivariate and multivariable binary logistic regression analyses were performed to identify independent predictors of treatment delay (>2 weeks) and incomplete treatment regimens. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) are reported. Results: A total of 244 patients were enrolled in the study. The study population was predominantly female (59.0%) and aged ≥60 years (60.2%). Advanced disease was common, with 50.4% of patients presenting with stage IV disease. Financial vulnerability was widespread: 72.6% reported monthly household incomes below USD 1000, 88.1% reported a decline in income due to the economic crisis, and 39.3% relied on unstable income sources. Overall, 52.5% of patients experienced treatment initiation delays, and 9.0% received incomplete or dose-reduced regimens. On multivariable analysis, reliance on unfixed income independently predicted treatment delay (aOR 2.55, 95% CI 1.42–4.59; p = 0.002), lack of health insurance (aOR 1.91, 95% CI 1.08–3.39; p = 0.026) and pre-treatment surgical costs also increased the odds of delay (aOR 9.03, 95% CI 2.57–31.7; p = 0.001). For incomplete treatment, unfixed income remained an independent predictor (aOR 2.09, 95% CI 1.16–5.79; p = 0.015). A lack of insurance (aOR 5.62, 95% CI 1.22–25.9; p = 0.027) and high laboratory costs (>USD 150 per session) were also associated with incomplete regimens (aOR 1.62, 95% CI 1.02–2.57; p = 0.041). Conclusions: In Lebanon’s crisis context, financial instability was a key factor associated with deviations in cancer treatment. These findings highlight the need for strengthened insurance coverage and subsidization of diagnostic and treatment-related costs to ensure timely and continuous oncologic care. Full article

Circadian rhythms regulate key biological processes central to cancer biology, including cell cycle control, DNA repair, metabolism, immune function, and drug pharmacokinetics. Experimental models consistently demonstrate marked time-of-day differences in the efficacy and toxicity of chemotherapy, targeted agents, and immunotherapies. Clinical studies of chronomodulated chemotherapy—particularly with fluoropyrimidines, platinum compounds, and anthracyclines—show reproducible reductions in treatment-related toxicity, while effects on survival outcomes remain variable and often sex dependent. Emerging clinical evidence also suggests that timing of immune checkpoint inhibitor administration may influence progression-free and overall survival across several tumor types. However, translation into routine oncology practice has been limited by interindividual variability in circadian phase, tumor-specific disruption of clock function, lack of validated biomarkers, and logistical constraints of time-specific drug delivery. Advances in circadian phenotyping, wearable monitoring, and adaptive dosing technologies now offer feasible pathways toward individualized, biology-driven treatment timing. This narrative review critically evaluates mechanistic, preclinical, and clinical evidence for chronotherapy across oncological treatment modalities and examines challenges and opportunities for its integration into precision cancer care. Full article

Background/Objectives: Colorectal cancer (CRC) remains a major contributor to the global oncological burden, with marked disparities in mortality and survival between Western and Eastern European countries. Romania continues to report unfavorable CRC outcomes, driven by delayed diagnosis, limited screening uptake, and heterogeneous care pathways. This study aimed to assess the 15-year institutional description of colorectal cancer case-mix in South-West Oltenia, Romania, using real-world data from a high-volume oncology referral center. Methods: We conducted a retrospective observational study including 3497 patients with newly diagnosed CRC registered between 2011 and 2025. Sociodemographic characteristics, tumor localization, stage at diagnosis, and histopathological grade were analyzed. Temporal patterns were assessed across three five-year intervals. Results: The institutional CRC case volume increased, with 434 cases recorded in 2011–2015, 1015 in 2016–2020, and 2048 in 2021–2025. Male patients accounted for 60.5% and urban residents for 60.3% of cases. Early-onset CRC was identified in 12.0% of patients, with no significant temporal trend. Rectosigmoid junction/rectal cancers represented the largest anatomical group, followed by left-sided cancers, with stable distribution across periods. Advanced stage disease was frequent, with 77.1% of patients diagnosed in stage III–IV, increasing from 67.7% to 82.0% across study intervals (p < 0.001). Histopathological grade changed significantly (p < 0.001), due to a progressive increase in unspecified grade, from 16.1% to 45.5%. Conclusions: Colorectal cancer represents a substantial institutional workload at this regional referral center, emphasizing the need for strengthened early detection strategies, optimized referral system, improved diagnostic access, and standardized pathological reporting practices. Full article

Background/Objectives: Schlafen 11 (SLFN11) encodes a DNA damage response protein implicated in sensitivity to DNA-damaging therapies and has been proposed as a predictive biomarker in several malignancies. This study aimed to characterize SLFN11 expression and evaluate its prognostic and predictive significance in locally advanced rectal cancer (LARC). Methods: Publicly available datasets were interrogated using UCSC Xena, GEPIA2, TNMplot, KMplot, ROC Plotter, and GEO databases. SLFN11 expression was assessed by quantitative real-time PCR in paired tumor and adjacent non-tumor tissues collected before and after neoadjuvant chemoradiotherapy (nCRT) from 26 patients with LARC. Associations with clinicopathological characteristics, pathological response, and survival outcomes were analyzed. Results: Publicly available datasets demonstrated lower SLFN11 expression in rectal tumor tissues compared with non-tumor tissues. In our cohort, no significant differences in SLFN11 expression were observed between paired tumor and adjacent non-tumor tissues either before or after nCRT. However, SLFN11 expression increased significantly following nCRT in both tissue types. Nevertheless, neither bioinformatic analyses nor our cohort demonstrated a significant association between SLFN11 expression and survival outcomes. Likewise, no significant predictive value of SLFN11 expression for response to nCRT was observed in ROC Plotter analysis, most GEO datasets, or our clinical cohort. The prognostic and predictive findings should be considered exploratory due to limited statistical power. Conclusions: Although SLFN11 expression is reduced in rectal tumor tissues and appears to be influenced by nCRT, its prognostic and predictive value in LARC remains uncertain. Larger studies are warranted to clarify its biological and clinical significance. Full article

Background/Objective: Cinnamaldehyde (CA) is a naturally occurring bioactive compound derived from the leaves, bark, roots, and flowers of the Chinese medicinal plant Cinnamomum cassia. It exhibits a broad spectrum of pharmacological properties, encompassing antioxidant, antibacterial, anti-diabetic, antifungal, and anticancer activities. Notably, it has shown potential therapeutic benefits in the management of type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). Ochratoxin A (OTA), a common contaminant found in foods such as cereals, coffee, and raisins, is also present in traditional Chinese medicinal materials, including Astragalus and liquorice. T2DM and NAFLD share intertwined pathophysiological pathways, including insulin resistance, dyslipidaemia, chronic low-grade inflammation and oxidative stress, with insulin resistance serving as the common pathological hub for both conditions. Consequently, they frequently co-occur and exacerbate each other. OTA exerts dual-targeted toxicity to the pancreas and liver, which may synergistically drive the development of the comorbidity of T2DM and NAFLD. These two processes are mutually causal and together constitute the pathological basis of metabolic comorbidity. Methods: Network toxicology employs toxicological data, gene expression, and protein–protein interaction (PPI) networks to predict the targets of toxins, while network pharmacology, based on systems biology principles, reveals how drugs exert regulatory effects through multiple targets and pathways. In this study, we employed an integrated network toxicology and network pharmacology approach to jointly decipher the potential mechanisms by which CA intervenes in OTA-induced comorbid T2DM-NAFLD. First, a network toxicology approach was employed to preliminarily screen for core toxicological targets responsible for OTA’s pathogenicity. Subsequently, network pharmacology was used to identify potential targets of CA-mediated intervention in the disease. Finally, the common overlap among the CA intervention targets, OTA toxicity targets, and disease targets was defined as the final set of potential targets for CA-mediated intervention in OTA-induced T2DM-NAFLD comorbidity. A PPI network was constructed using the STRING database, and topological analysis was performed with Cytoscape. Core targets were selected using the median values of six parameters—betweenness centrality, closeness centrality, degree centrality, eigenvector centrality, LAC (local average connectivity) score, and network centrality—as cut-off thresholds, and the top 10 key genes were further identified using the cytoHubba plugin. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via the DAVID database, and the results were visualized on the CNSknowall platform. Lastly, molecular docking of the core targets was performed using the CB-DOCK2 platform to validate binding affinity. Results: Based on an integrated analysis of network toxicology, network pharmacology, and molecular docking, 10 key targets were systematically identified. These may serve as potential mediators of cinnamaldehyde in the treatment of OTA-induced T2DM-NAFLD comorbidity. Among these, six targets—albumin (ALB), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), interleukin-6 (IL-6), tumor necrosis factor (TNF), actin beta (ACTB), and estrogen receptor 1 (ESR1)—possess crystal structures amenable to molecular docking. KEGG enrichment analysis revealed that CA and OTA jointly participate in key pathological processes such as the cancer pathway, the lipid and atherosclerosis pathway, the advanced glycation end-products–receptor for advanced glycation end-products (AGE-RAGE) signaling pathway, the phosphatidylinositol 3-kinase–protein kinase B (PI3K-Akt) signaling pathway, the TNF signaling pathway, and the interleukin-17 (IL-17) signaling pathway. OTA exacerbates inflammatory responses, impairs insulin signaling, promotes hepatic steatosis, and disrupts systemic metabolic homeostasis, ultimately contributing to T2DM-NAFLD comorbidity. Conversely, cinnamaldehyde counteracts these pathological processes through multiple mechanisms, including antioxidant and anti-inflammatory effects as well as regulation of glucose and lipid metabolism, thereby restoring metabolic homeostasis. Conclusions: This study has preliminarily identified the toxicological targets of OTA and the potential intervention targets of CA, offering new avenues for preventing and intervening in OTA-induced metabolic toxicity. Furthermore, it provides a theoretical basis for CA as a potential multi-target therapeutic agent and presents novel insights worthy of further investigation into the prevention of T2DM-NAFLD comorbidity. Full article

Advances in machine learning, predictive analytics, and clinical prediction modeling have accelerated the development of algorithmic tools for estimating reproductive outcomes after cancer treatment. In female oncofertility counseling, these models may support individualized assessment of treatment-related amenorrhea, premature ovarian insufficiency, and fertility risk, thereby improving risk communication and timely fertility-preservation referral. However, their use raises ethical concerns beyond predictive accuracy. This narrative review examines algorithmic prognostication in female oncofertility counseling, focusing on predictive uncertainty, surrogate reproductive endpoints, missing data, heterogeneous datasets, limited external validation, algorithmic bias, reproductive inequity, and the influence of algorithmic authority on patient autonomy and shared decision-making. We argue that predictive algorithms should be understood as decision-support tools rather than determinants of reproductive futures. Responsible implementation requires transparency, explainability, fairness assessment, ongoing validation, and meaningful human oversight. Algorithmic risk estimates should be communicated as conditional and contextual probabilities within patient-centered counseling, ensuring that predictive tools support informed, transparent, and value-concordant fertility-preservation decisions for women facing cancer treatment. Full article

Helicobacter pylori is one of the most common bacterial pathogens in humans and the primary etiological agent of chronic gastritis, peptic ulcer disease, and gastric cancer. Its ability to establish persistent gastric colonization relies on multiple virulence factors, including adhesins, urease, cytotoxins, motility, outer membrane vesicles, and biofilm formation, which collectively promote bacterial survival, chronic inflammation, and treatment failure. The increasing prevalence of antibiotic-resistant H. pylori strains has intensified the search for therapeutic strategies targeting both bacterial viability and virulence. Berberine (BBR), a natural isoquinoline alkaloid, has emerged as a promising candidate because of its antibacterial, anti-inflammatory, and antioxidant properties. Increasing evidence derived from native berberine, its derivatives, and berberine-based formulations indicates multifaceted anti-H. pylori activity, including direct antibacterial effects, inhibition of virulence determinants, and modulation of host inflammatory responses. This review summarizes current knowledge on the epidemiology and pathogenic mechanisms of H. pylori and provides a comprehensive overview of the available evidence regarding the anti-H. pylori pharmacological profile of BBR-based compounds. Particular attention is given to their effects on bacterial adhesion, motility, urease activity, efflux pump function, biofilm formation, and host inflammatory signaling pathways. The review also discusses findings from preclinical and clinical studies supporting BBR-based strategies as adjuncts to conventional eradication therapies. In addition, recent advances in nanotechnology-based drug delivery systems designed to overcome the poor oral bioavailability of BBR and improve its therapeutic efficacy against H. pylori are highlighted. Full article

Background: We assessed the prognostic value of the pan-immune–inflammation value (PIV), systemic immune–inflammation index (SII), lung immune prognostic index (LIPI), and c-reactive protein–albumin–lymphocyte (CALLY) index in advanced non-small cell lung cancer (NSCLC) treated with first-line immune checkpoint inhibitor (ICI)-based therapy. Methods: This multicenter retrospective study included 161 patients who received ICI monotherapy, chemoimmunotherapy, or dual ICI therapy. The objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression models. Results: A high CALLY index was associated with a significantly higher CBR (82.1% vs. 59.5%; p = 0.015), longer PFS (14.95 vs. 7.13 months; p = 0.002), and longer OS (25.79 vs. 13.24 months; p = 0.003). In the multivariable analyses, a high CALLY index remained independently associated with improved PFS (HR = 0.52, p = 0.006) and OS (HR = 0.53, p = 0.010), whereas a high SII was independently associated with poorer PFS (HR = 1.74, p = 0.021) and OS (HR = 1.90, p = 0.009). PIV and LIPI were not independently associated with survival outcomes. Conclusions: SII and the CALLY index emerged as independent prognostic biomarkers in advanced NSCLC receiving first-line immunotherapy-based treatment. The CALLY index showed the strongest and most consistent association with clinical benefit, PFS, and OS. Full article

Background/Objectives: High-grade serous carcinoma (HGSC) represents the most frequent subtype of epithelial ovarian cancer (OC) and is associated with malignant ascitic fluid (MAF), which fosters a pro-inflammatory microenvironment that supports tumor progression. Given its rich cellular and soluble content, MAF offers a valuable window into tumor–host interactions and disease dynamics. This study examines the immune landscape of MAF samples from 22 newly diagnosed treatment-naïve HGSC patients. Methods: Immune cell phenotypes and cytokine profiles were analyzed via flow cytometry. Patients were stratified according to time to death or recurrence (TDR), using a six-month interval from diagnosis to either documented recurrence or disease-specific death as the cutoff: TDR < 6 months defined as the worse prognosis group, whereas TDR ≥ 6 months defined the better prognosis group. The expression of immune checkpoint molecules on T cells and the effects of PD-1 blockade with Pembrolizumab were also assessed. Results: Patients with worst prognosis exhibited a marked pro-inflammatory cytokine milieu, with elevated levels of TNFα, IL-1β, IL-23, and IFNγ. Concurrently, their CD4⁺ and CD8⁺ T cells displayed evidence of a functional exhaustion-associated phenotype, marked by heightened expression of the inhibitory receptors TIM-3, PD-1, and LAG-3. Notably, treatment with Pembrolizumab (a PD-1 checkpoint inhibitor) significantly enhance T cell effector function. Conclusions: These results underscore a potential immunotherapeutic approach in anti-tumor immunity among selected HGSC patients, presenting a compelling direction for advancing OC treatment. 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